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PHYSIOLOGICAL PSYCHOLOGY
B.Sc. in Counselling Psychology
Complementary Course
I Semester
(2011 Admission onwards)
UNIVERSITY OF CALICUT
SCHOOL OF DISTANCE EDUCATION
Calicut University P.O. Malappuram, Kerala, India 673 635
School of Distance Education
UNIVERSITY OF CALICUT
SCHOOL OF DISTANCE EDUCATION
B.Sc in Counselling Psychology
I Semester
Complimentary Course
PHYSIOLOGICAL PSYCHOLOGY
Prepared and
scrutinised by :
Layout:
Prof. (Dr.) C. Jayan
Department of Psychology
University of Calicut
Computer Section, SDE
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CONTENTS
PAGE
MODULE 1
Introduction-The three approaches to
brain
5 - 12
MODULE 2
Cellular Basis of Behaviour
13 - 47
MODULE 3
The Neuron
48 - 90
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MODULE 1
Introduction
THE THREE APPROACHES TO BRAIN
Ablation
Ablation means removal of material from the surface of an object by vaporization, chipping, or
other erosive processes. The term occurs in spaceflight associated with atmospheric reentry, in
glaciology, medicine, and passive fire protection.
Spaceflight
In spacecraft design, ablation is used to both cool and protect mechanical parts and/or payloads that
would otherwise be damaged by extremely high temperatures. Two principal applications are heat
shields for spacecraft entering a planetary atmosphere from space and cooling of rocket engine
nozzles. Examples include the Apollo Command Module that protected astronauts from the heat of
atmospheric reentry and the Kestrel second stage rocket engine designed for exclusive use in an
environment of space vacuum since no heat convection is possible.
In a basic sense, ablative material is designed to slowly burn away in a controlled manner, so that
heat can be carried away from the spacecraft by the gases generated by the ablative process; while
the remaining solid material insulates the craft from superheated gases. There is an entire branch of
spaceflight research involving the search for new fireproofing materials to achieve the best ablative
performance; this function is critical to protect the spacecraft occupants and payload from
otherwise excessive heat loading. The same technology is used in some passive fire protection
applications, in some cases by the same vendors, who offer different versions of these fireproofing
products, some for aerospace and some for structural fire protection.
Glaciology
In glaciology, ablation refers to processes that remove snow and ice from a glacier. Ablation may
refer to the melting of snow or ice that runs off the glacier, evaporation, sublimation, calving, or
removal of snow by wind.
Medicine
In medicine, ablation is the same as removal of a part of biological tissue, usually by surgery.
Surface ablation of the skin (dermabrasion, also called resurfacing because it induces regeneration)
can be carried out by chemicals (which cause peeling) or by lasers. Its purpose is to remove skin
spots, aged skin, wrinkles, thus rejuvenating it. Surface ablation is also employed in otolaryngology
for several kinds of surgery, such as for snoring. Ablation therapy using radio frequency waves on
the heart is used to cure a variety of cardiac arrhythmia such as supraventricular tachycardia,
Wolff-Parkinson-White syndrome (WPW), ventricular tachycardia, and more recently as
management of atrial fibrillation. The term is often used in the context of laser ablation, a process
in which a laser dissolves a material's molecular bonds. For a laser to ablate tissues, the power
density or fluence must be high, otherwise thermocoagulation occurs, which is simply thermal
vaporization of the tissues.
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Rotoablation is a type of arterial cleansing that consists of inserting a tiny, diamond-tipped, drilllike device into the affected artery to remove fatty deposits or plaque. The procedure is used in the
treatment of coronary heart disease to restore blood flow.
Radio frequency ablation is a method of removing aberrant tissue from within the body via
minimally invasive procedures. i.e.RF ablation in an Electrophysiology study to remove cells that
are issuing abnormal electrical activity leading to arrhythmia.
Bone marrow ablation is a process whereby the human bone marrow cells are eliminated in
preparation for a bone marrow transplant. This is performed using high-intensity chemotherapy and
total body irradiation. As such it has nothing to do with the vaporization techniques described in the
rest of this article.
Ablation of brain tissue is used for treating certain neurological disorders, particularly Parkinson's
disease, and sometimes for psychiatric disorders as well.
Recently, some researchers reported successful results with genetic ablation. In particular, genetic
ablation is potentially a much more efficient method of removing unwanted cells, such as tumor
cells, because large numbers of animals lacking specific cells could be generated. Genetically
ablated lines can be maintained for a prolonged period of time and shared within the research
community. Researchers at Columbia University report of reconstituted caspases combined from C.
elegans and humans, which maintain a high degree of target specificity. The genetic ablation
techniques described could prove useful in battling cancer.
Biology
Ablation in biology can refer to genetic or cell ablation, for example. Genetic ablation describes a
gene that has been silenced. It can be used on purpose in experiments where scientists can observe
the effect of genetic silencing. Cell ablation is where individual cells are destroyed for experimental
reasons.
Laser ablation
Laser ablation is greatly affected by the nature of the material and its ability to absorb energy,
therefore the wavelength of the ablation laser should have a minimum absorption depth.
Surface ablation of the cornea for several types of eye refractive surgery is now common, using an
excimer laser system (LASIK and LASEK). Since the cornea does not grow back, laser is used to
remodel the cornea refractive properties to correct refraction errors, such as astigmatism, myopia,
and hyperopia. Laser ablation is also used to remove part of the uterine wall in women with
menstruation and adenomyosis problems in a process called endometrial ablation.
Passive fire protection
Firestopping and fireproofing products can be ablative in nature. This can mean endothermic
materials, or merely materials that are sacrificial and become "spent" over time while exposed to
fire such as silicone firestop products. Given sufficient time under fire or heat conditions, these
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products char away, crumble, and disappear. The idea is to put enough of this material in the way of
the fire that a level of fire-resistance rating can be maintained, as demonstrated in a fire test.
Ablative materials usually have a large concentration of organic matter[citation needed] that is
reduced by fire to ashes. In the case of silicone, organic rubber surrounds very finely divided silica
dust (up to 380 m² of combined surface area of all the dust particles per gram of this dust[citation
needed]). When the organic rubber is exposed to fire it burns to ash and leaves behind the silica
dust with which the product started.
Marine Surface Coatings
Antifouling paints and other related coatings are routinely used to prevent the buildup of
microorganisms and other animals, such as barnacles for the bottom hull surfaces of recreational,
commercial and military sea vessels. Ablative paints are often utilized for this purpose to prevent
the dilution or deactivation of the antifouling agent. Over time, the paint will slowly decompose in
the water, exposing fresh antifouling compounds on the surface. Engineering the antifouling agents
and the ablation rate can produce long-lived protection from the deleterious effects of biofouling.
Stimulation
Stimulation is the action of various agents (stimuli) on muscles, nerves, or a sensory end organ, by
which activity is evoked; especially, the nervous impulse produced by various agents on nerves, or
a sensory end organ, by which the part connected with the nerve is thrown into a state of activity.
The word is also often used metaphorically. For example, an interesting or fun activity can be
described as "stimulating", regardless of its physical effects on nerves.
It is also used in simulation technology to describe a synthetically-produced signal that triggers
(stimulates) real equipment, see below.
Overview
Stimulation in general refers to how organisms perceive incoming stimuli. As such it is part of
the stimulus-response mechanism. Simple organisms broadly react in three ways to stimulation: too
little stimulation causes them to stagnate, too much to die from stress or inability to adapt, and a
medium amount causes them to adapt and grow as they overcome it. Similar categories or effects
are noted with psychological stress with people. Thus, stimulation may be described as how
external events provoke a response by an individual in the attempt to cope.
Use in Simulators and Simulation Technology Stimulation describes a type of simulation
whereby artificially-generated signals are fed to real equipment or software in order to Stimulate it
to produce the result required for training, maintenance or for R&D. The real equipment can be
radar, sonics, instruments, software and so on. In some cases the Stimulation equipment can be
carried in the real platform or carriage vehicle (that is the Ship, AFV or Aircraft) and be used for
so-called "embedded training" during its operation, by the generation of simulated scenarios which
can be dealt with in a realistic manner by use of the normal controls and displays. In the overall
definition of simulation, the alternative method is called "emulation" which is the simulation of
equipment by entirely artificial means by physical and software modelling.
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Over-stimulation
Psychologically, it is possible to become habituated to a degree of stimulation, and then find it
uncomfortable to have significantly more or less. Thus one can become used to an intense life, or
television, and suffer withdrawal when they are removed, from lack of stimulation, and it is
possible to also be unhappy and stressed due to additional abnormal stimulation.
It is hypothesized and commonly believed by some that psychological habituation to a high level of
stimulation ("over-stimulation") can lead to psychological problems. For example, some food
additives can result in children becoming prone to over-stimulation, and ADHD is, theoretically, a
condition in which over-stimulation is a part. It is also hypothesized that long term over-stimulation
can result eventually in a phenomenon called "adrenal exhaustion" over time, but this is not
medically accepted or proven at this time.
What is sure is that ongoing, long term stimulation, can for some individuals prove harmful, and a
more relaxed and less stimulated life may be beneficial.
Recording
Recording is a process of capturing data or translating information to a format stored on a storage
medium often referred to as a record.
Ways of recording text suitable for direct reading by humans includes writing it on paper. Other
forms of data storage are easier for automatic retrieval, but humans need a tool to read them.
Printing a text stored in a computer allows keeping a copy on the computer and having also a copy
that is human-readable without a tool.
Technology continues to provide and expand means for human beings to represent, record and
express their thoughts, feelings and experiences.
New Techniques in this Field
History
In 1918 the American neurosurgeon Walter Dandy introduced the technique of ventriculography.
X-ray images of the ventricular system within the brain were obtained by injection of filtered air
directly into one or both lateral ventricles of the brain. Dandy also observed that air introduced into
the subarachnoid space via lumbar spinal puncture could enter the cerebral ventricles and also
demonstrate the cerebrospinal fluid compartments around the base of the brain and over its surface.
This technique was called pneumoencephalography.
In 1927 Egas Moniz introduced cerebral angiography, whereby both normal and abnormal blood
vessels in and around the brain could be visualized with great precision.
In the early 1970s, Allan McLeod Cormack and Godfrey Newbold Hounsfield introduced
computerized axial tomography (CAT or CT scanning), and ever more detailed anatomic images of
the brain became available for diagnostic and research purposes. Cormack and Hounsfield won the
1979 Nobel Prize for Physiology or Medicine for their work. Soon after the introduction of CAT in
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the early 1980s, the development of radioligands allowed single photon emission computed
tomography (SPECT) and positron emission tomography (PET) of the brain.
More or less concurrently, magnetic resonance imaging (MRI or MR scanning) was developed by
researchers including Peter Mansfield and Paul Lauterbur, who were awarded the Nobel Prize for
Physiology or Medicine in 2003. In the early 1980s MRI was introduced clinically, and during the
1980s a veritable explosion of technical refinements and diagnostic MR applications took place.
Scientists soon learned that the large blood flow changes measured by PET could also be imaged
by the correct type of MRI. Functional magnetic resonance imaging (fMRI) was born, and since the
1990s, fMRI has come to dominate the brain mapping field due to its low invasiveness, lack of
radiation exposure, and relatively wide availability. As noted above fMRI is also beginning to
dominate the field of stroke treatment.
In early 2000s the field of neuroimaging reached the stage where limited practical applications of
functional brain imaging have become feasible. The main application area is crude forms of braincomputer interface.
Brain imaging techniques
Computed axial tomography
Computed tomography (CT) or Computed Axial Tomography (CAT) scanning uses a series of
x-rays of the head taken from many different directions. Typically used for quickly viewing brain
injuries, CT scanning uses a computer program that performs a numerical integral calculation (the
inverse Radon transform) on the measured x-ray series to estimate how much of an x-ray beam is
absorbed in a small volume of the brain. Typically the information is presented as cross sections of
the brain.
In approximation, the denser a material is, the whiter a volume of it will appear on the scan (just as
in the more familiar "flat" X-rays). CT scans are primarily used for evaluating swelling from tissue
damage in the brain and in assessment of ventricle size. Modern CT scanning can provide
reasonably good images in a matter of minutes.
Diffuse optical imaging
Diffuse optical imaging (DOI) or diffuse optical tomography (DOT) is a medical imaging modality
which uses near infrared light to generate images of the body. The technique measures the optical
absorption of haemoglobin, and relies on the absorption spectrum of haemoglobin varying with its
oxygenation status.
Event-related optical signal
Event-related optical signal (EROS) is a brain-scanning technique which uses infrared light through
optical fibers to measure changes in optical properties of active areas of the cerebral cortex.
Whereas techniques such as diffuse optical imaging (DOT) and near infrared spectroscopy (NIRS)
measure optical absorption of haemoglobin, and thus are based on blood flow, EROS takes
advantage of the scattering properties of the neurons themselves, and thus provides a much more
direct measure of cellular activity. EROS can pinpoint activity in the brain within millimeters
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(spatially) and within milliseconds (temporally). Its biggest downside is the inability to detect
activity more than a few centimeters deep. EROS is a new, relatively inexpensive technique that is
non-invasive to the test subject. It was developed at the University of Illinois at Urbana-Champaign
where it is now used in the Cognitive Neuroimaging Laboratory of Dr. Gabriele Gratton and Dr.
Monica Fabiani.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) uses magnetic fields and radio waves to produce high quality
two- or three-dimensional images of brain structures without use of ionizing radiation (X-rays) or
radioactive tracers. During an MRI, a large cylindrical magnet creates a magnetic field around the
head of the patient through which radio waves are sent. When the magnetic field is imposed, each
point in space has a unique radio frequency at which the signal is received and transmitted (Preuss).
Sensors read the frequencies and a computer uses the information to construct an image. The
detection mechanisms are so precise that changes in structures over time can be detected.
Using MRI, scientists can create images of both surface and subsurface structures with a high
degree of anatomical detail. MRI scans can produce cross sectional images in any direction from
top to bottom, side to side, or front to back. The problem with original MRI technology was that
while it provides a detailed assessment of the physical appearance, water content, and many kinds
of subtle derangements of structure of the brain (such as inflammation or bleeding), it fails to
provide information about the metabolism of the brain (i.e. how actively it is functioning) at the
time of imaging. A distinction is therefore made between "MRI imaging" and "functional MRI
imaging" (fMRI), where MRI provides only structural information on the brain while fMRI yields
both structural and functional data.
Functional magnetic resonance imaging
Axial MRI slice at the level of the basal ganglia, showing fMRI BOLD signal changes overlayed in
red (increase) and blue (decrease) tones.
Functional magnetic resonance imaging (fMRI) relies on the paramagnetic properties of
oxygenated and deoxygenated hemoglobin to see images of changing blood flow in the brain
associated with neural activity. This allows images to be generated that reflect which brain
structures are activated (and how) during performance of different tasks.
Most fMRI scanners allow subjects to be presented with different visual images, sounds and touch
stimuli, and to make different actions such as pressing a button or moving a joystick. Consequently,
fMRI can be used to reveal brain structures and processes associated with perception, thought and
action. The resolution of fMRI is about 2-3 millimeters at present, limited by the spatial spread of
the hemodynamic response to neural activity. It has largely superseded PET for the study of brain
activation patterns. PET, however, retains the significant advantage of being able to identify
specific brain receptors (or transporters) associated with particular neurotransmitters through its
ability to image radiolabelled receptor "ligands" (receptor ligands are any chemicals that stick to
receptors).
As well as research on healthy subjects, fMRI is increasingly used for the medical diagnosis of
disease. Because fMRI is exquisitely sensitive to blood flow, it is extremely sensitive to early
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changes in the brain resulting from ischemia (abnormally low blood flow), such as the changes
which follow stroke. Early diagnosis of certain types of stroke is increasingly important in
neurology, since substances which dissolve blood clots may be used in the first few hours after
certain types of stroke occur, but are dangerous to use afterwards. Brain changes seen on fMRI may
help to make the decision to treat with these agents. With between 72% and 90% accuracy where
chance would achieve 0.8%, fMRI techniques can decide which of a set of known images the
subject is viewing.
Electroencephalography
Electroencephalography (EEG) is an imaging technique used to measure the electric fields in the
brain via electrodes placed on the scalp of a human. EEG offers a very direct measurement of
neural electrical activity with very high temporal resolution but relatively low spatial resolution.
Magnetoencephalography
Magnetoencephalography (MEG) is an imaging technique used to measure the magnetic fields
produced by electrical activity in the brain via extremely sensitive devices such as superconducting
quantum interference devices (SQUIDs). MEG offers a very direct measurement neural electrical
activity (compared to fMRI for example) with very high temporal resolution but relatively low
spatial resolution. The advantage of measuring the magnetic fields produced by neural activity is
that they are not distorted by surrounding tissue, unlike the electric fields measured by EEG
(particularly the skull and scalp).
There are many uses for the MEG, including assisting surgeons in localizing a pathology, assisting
researchers in determining the function of various parts of the brain, neurofeedback, and others.
Positron emission tomography
Positron emission tomography (PET) measures emissions from radioactively labeled metabolically
active chemicals that have been injected into the bloodstream. The emission data are computerprocessed to produce 2- or 3-dimensional images of the distribution of the chemicals throughout the
brain. The positron emitting radioisotopes used are produced by a cyclotron, and chemicals are
labeled with these radioactive atoms. The labeled compound, called a radiotracer, is injected into
the bloodstream and eventually makes its way to the brain. Sensors in the PET scanner detect the
radioactivity as the compound accumulates in various regions of the brain. A computer uses the
data gathered by the sensors to create multicolored 2- or 3-dimensional images that show where the
compound acts in the brain. Especially useful are a wide array of ligands used to map different
aspects of neurotransmitter activity, with by far the most commonly used PET tracer being a
labeled form of glucose (see FDG).
The greatest benefit of PET scanning is that different compounds can show blood flow and oxygen
and glucose metabolism in the tissues of the working brain. These measurements reflect the amount
of brain activity in the various regions of the brain and allow to learn more about how the brain
works. PET scans were superior to all other metabolic imaging methods in terms of resolution and
speed of completion (as little as 30 seconds), when they first became available. The improved
resolution permitted better study to be made as to the area of the brain activated by a particular task.
The biggest drawback of PET scanning is that because the radioactivity decays rapidly, it is limited
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to monitoring short tasks. Before fMRI technology came online, PET scanning was the preferred
method of functional (as opposed to structural) brain imaging, and it still continues to make large
contributions to neuroscience.
PET scanning is also used for diagnosis of brain disease, most notably because brain tumors,
strokes, and neuron-damaging diseases which cause dementia (such as Alzheimer's disease) all
cause great changes in brain metabolism, which in turn causes easily detectable changes in PET
scans. PET is probably most useful in early cases of certain dementias (with classic examples being
Alzheimer's disease and Pick's disease) where the early damage is too diffuse and makes too little
difference in brain volume and gross structure to change CT and standard MRI images enough to
be able to reliably differentiate it from the "normal" range of cortical atrophy which occurs with
aging (in many but not all) persons, and which does not cause clinical dementia.
Single photon emission computed tomography
Single photon emission computed tomography (SPECT) is similar to PET and uses gamma ray
emitting radioisotopes and a gamma camera to record data that a computer uses to construct two- or
three-dimensional images of active brain regionsSPECT relies on an injection of radioactive tracer,
which is rapidly taken up by the brain but does not redistribute. Uptake of SPECT agent is nearly
100% complete within 30 – 60s, reflecting cerebral blood flow (CBF) at the time of injection.
These properties of SPECT make it particularly well suited for epilepsy imaging, which is usually
made difficult by problems with patient movement and variable seizure types. SPECT provides a
"snapshot" of cerebral blood flow since scans can be acquired after seizure termination (so long as
the radioactive tracer was injected at the time of the seizure). A significant limitation of SPECT is
its poor resolution (about 1 cm) compared to that of MRI.
Like PET, SPECT also can be used to differentiate different kinds of disease processes which
produce dementia, and it is increasingly used for this purpose. Neuro-PET has a disadvantage of
requiring use of tracers with half-lives of at most 110 minutes, such as FDG. These must be made
in a cyclotron, and are expensive or even unavailable if necessary transport times are prolonged
more than a few half-lives. SPECT, however, is able to make use of tracers with much longer halflives, such as technetium-99m, and as a result, is far more widely available.
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Module 2
CELLULAR BASIS OF BEHAVIOUR
Receptors
Receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a
cell, to which one or more specific kinds of signaling molecules may attach. A molecule which
binds (attaches) to a receptor is called a ligand, and may be a peptide (short protein) or other small
molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. Each kind of
receptor can bind only certain ligand shapes. Each cell typically has many receptors, of many
different kinds.
Ligand binding stabilizes a certain receptor conformation (the three-dimensional shape of the
receptor protein, with no change in sequence). This is often associated with gain of or loss of
protein activity, ordinarily leading to some sort of cellular response. However, some ligands (e.g.
antagonists) merely block receptors without inducing any response. Ligand-induced changes in
receptors result in cellular changes which constitute the biological activity of the ligands. Many
functions of the human body are regulated by these receptors responding uniquely to specific
molecules like this.
Overview
The shapes and actions of receptors are studied by X-ray crystallography, dual polarisation
interferometry, computer modelling, and structure-function studies, which have advanced the
understanding of drug action at the binding sites of receptors. Structure activity relationships
correlate induced conformational changes with biomolecular activity, and are studied using
dynamic techniques such as circular dichroism and dual polarisation interferometry.
Depending on their functions and ligands, several types of receptors may be identified:
* Some receptor proteins are peripheral membrane proteins.
* Many hormone and neurotransmitter receptors are transmembrane proteins: transmembrane
receptors are embedded in the phospholipid bilayer of cell membranes, that allow the
activation of signal transduction pathways in response to the activation by the binding
molecule, or ligand.
o Metabotropic receptors are coupled to G proteins and affect the cell indirectly through enzymes
which control ion channels.
o Ionotropic receptors (also known as ligand-gated ion channels) contain a central pore which
opens in response to the binding of ligand.
* Another major class of receptors are intracellular proteins such as those for steroid and
intracrine peptide hormone receptors. These receptors often can enter the cell nucleus and modulate
gene expression in response to the activation by the ligand.
Membrane receptors are isolated from cell membranes by complex extraction procedures using
solvents, detergents, and/or affinity purification.
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Binding and activation
Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them
according to the law of mass action.
One measure of how well a molecule fits a receptor is the binding affinity, which is inversely
related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The
final biological response (e.g. second messenger cascade or muscle contraction), is only achieved
after a significant number of receptors are activated.
The receptor-ligand affinity is greater than enzyme-substrate affinity. Whilst both interactions are
specific and reversible, there is no chemical modification of the ligand as seen with the substrate
upon binding to its enzyme.
Constitutive activity
A receptor which is capable of producing its biological response in the absence of a bound ligand
is said to display "constitutive activity". The constitutive activity of receptors may be blocked by
inverse agonist binding. Mutations in receptors that result in increased constitutive activity underlie
some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone
receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). For
the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity.
Agonists versus antagonists
Not every ligand that binds to a receptor also activates the receptor. The following classes of
ligands exist:
 (Full) agonists are able to activate the receptor and result in a maximal biological response.
Most natural ligands are full agonists.
 Partial agonists do not activate receptors thoroughly, causing responses which are partial
compared to those of full agonists.
 Antagonists bind to receptors but do not activate them. This results in receptor blockage,
inhibiting the binding of other agonists.
 Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.
Peripheral membrane protein receptors
These receptors are relatively rare compared to the much more common types of receptors that
cross the cell membrane. An example of a receptor that is a peripheral membrane protein is the
elastin receptor.
Transmembrane receptors
These receptors are also known as seven transmembrane receptors or 7TM receptors, because they
pass through the membrane seven times.
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* Muscarinic acetylcholine receptor (Acetylcholine and Muscarine)
* Adenosine receptors (Adenosine)
* Adrenoceptors (also known as Adrenergic receptors, for adrenaline, and other structurally
related hormones and drugs)
* GABA receptors, Type-B (γ-Aminobutyric acid or GABA)
* Angiotensin receptors (Angiotensin)
* Cannabinoid receptors (Cannabinoids)
* Cholecystokinin receptors (Cholecystokinin)
* Dopamine receptors (Dopamine)
* Glucagon receptors (Glucagon)
* Metabotropic glutamate receptors (Glutamate)
* Histamine receptors (Histamine)
* Olfactory receptors (for the sense of smell)
* Opioid receptors (Opioids)
* Protease-activated receptors
* Rhodopsin (a photoreceptor)
* Secretin receptors (Secretin)
* Serotonin receptors, except Type-3 (Serotonin, also known as 5-Hydroxytryptamine or 5-HT)
* Somatostatin receptors (Somatostatin)
* Calcium-sensing receptor (Calcium)
* Chemokine receptors (Chemokines)
* many more ...
Receptor tyrosine kinases
These receptors detect ligands and propagate signals via the tyrosine kinase of their intracellular
domains. This family of receptors includes;
* Erythropoietin receptor (Erythropoietin)
* Insulin receptor (Insulin)
* Eph receptors
* Insulin-like growth factor 1 receptor
* various other growth factor and cytokine receptors
Guanylyl cyclase receptors
* GC-A & GC-B: receptors for Atrial-natriuretic peptide (ANP) and other natriuretic peptides
* GC-C: Guanylin receptor
Ionotropic receptors
Ionotropic receptors are heteromeric or homomeric oligomers . They are receptors that respond to
extracellular ligands and receptors that respond to intracellular ligands.
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Role in Genetic Disorders
Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine
whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise
to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased
hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.
Receptor Regulation
Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given
hormone or neurotransmitter to alter its sensitivity to this molecule. This is a locally acting
feedback mechanism.
Effectors and conductor cells
Effector Cells of the Immune System
Monocytes circulate in the blood after leaving the bone marrow. Monocytes usually circulate in the
blood for only a day or so before they enter the tissue to mature into macrophages. Monocyte
production and release from the bone marrow is increased during an immune response. Under
normal conditions, monocytes enter the tissues as resident macrophages in various locations (such
as the skin, lung, liver, spleen, bone marrow and peritoneal cavity). These fixed, resident
macrophages play an important role in keeping the tissues clear of antigen and debris. More
monocytes are rapidly recruited as needed to these and other sites.
When monocytes enter the tissues and become macrophages they undergo several changes. The
cells enlarge, allowing greater phagocytosis and they increase the amount of digestive enzymes
(lysosyme) in their intracellular vesicles (lysosomes) thus facilitating microbe degradation. In the
tissues, macrophages live for months and are motile (using pseudopods to move like amoebae).
Macrophages are usually in the resting state unless activated during an immune response.
Activation of these cells may happen in response to Th-derived cytokines (especially IFNg) or from
contact with bacteria or bacterial products. Phagocytosis of pathogens also stimulates
activation. The activated state is characterized by more efficient phagocytosis and killing of
microbes.
There are three major roles that macrophages play in the immune response to pathogens. The first
is their very important role in phagocytosis. In this role they recognize and remove unwanted
particulate matter including products of inflammation and invading organisms, immune complexes,
toxins and dying cells. The large number of macrophages in the spleen and liver (where they are
called Kupffer cells) are particularly important for removal of bacteria from the bloodstream.
The second important role macrophages play is as antigen presenting cells (APC) during secondary
immune responses. Although they are very poor at activating naive T cells they are very good at
activating memory T cells. The great advantage of this is that circulating memory T cells which are
rapidly drawn to the site of infection can be immediately activated by macrophages without antigen
being transported to the local draining node for presentation to T cells. Their third role is cytokine
secretion. After activation, these cells secrete important inflammatory cytokines such as IL-1, IL-6
and TNF-a. IL-1 and TNF act to recruit neutrophils and more monocytes from the circulation as
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well as having systemic effects (such as fever). In chronic inflammation, macrophages act as
scavengers and can become giant cells (via cell fusion) which help form granulomas.
Natural Killer Cells
These cells are sometimes called large granular lymphocytes (LGL's) because they are large,
granular and lymphocytes (immunologists are so imaginative!). NK cells have some surface
markers in common with T cells, and they are also functionally similar to cytotoxic T lymphocytes
(CTL). Like CTL, NK cells are particularly important in the killing of cellular targets (such as
tumor cells or virus-infected cells). Unlike CTL, however, the killing by NK cells is not antigen
specific, they do not need to recognize specific antigen presented by MHC on the target cell. In
fact, it is the very presence or absence of Class I MHC that appears to be involved in NK cell
activation. It is thought that many tumor cells are too busy proliferating to bother about expressing
the normal surface molecules at normal levels. The lack of normal levels of Class I MHC on the
urface of tumor cells is sufficient to activate NK cells to kill them.
NK cells do not have a T cell receptor and are not T cells but they kill target cells in the same
manner as CTL kill targets (see above). However, they also produce large amounts of tumor
necrosis factor alpha (TNF-a). This factor has many functions but one important one in this
context is that it binds to the TNF receptor on target cells and induces apoptosis.
Recent data have shown that NK cells also produce a lot of IFN-g, which is very interesting since
this cytokine activates macrophages and stimulates them to produce large amounts of TNF-a.
Neutrophils
Neutrophils are produced in the bone marrow from the granulocyte-monocyte stem cell. These cells
are often called polymorphonuclear cells (PMN's). This is because of the polymorphic shape of the
nucleus. Sometimes the terms neutrophil and PMN are used interchangeably. Neutrophils are the
most common white blood cells in the circulation, making up about 60-70% of the total WBC
count. They are very short-lived cells, circulating in the blood for about 8 hours after their release
from the bone marrow. If induced to migrate out of the blood into the tissues, they will engage in a
variety of effector functions before dying by apoptosis within 1-2 days.
Neutrophils are attracted into the tissue by chemotactic factors that include Complement proteins,
clotting proteins, cytokines and chemokines. They are the first cells to arrive at the site of
inflammation by leaving the blood, through the endothelium into the tissue (called “transmigration”
or “emigration”). The appearance of neutrophils in the tissue is associated with bacterial infection,
acute tissue injury, immune complex-Complement activation, necrosis and tissue remodeling. In
the tissues, neutrophils are very active phagocytic cells. They are the most effective at killing
ingested microorganisms and can do this by oxygen dependent pathways (such as superoxide anion
[O2-] and hydrogen peroxide [H2O2]), nitrogen dependent pathways (nitric oxide [NO]) or
independent pathways (such as defensins and digestive enzymes). Neutrophils, however, do not
normally act as antigen presenting cells.
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Eosinophils
Eosinophils are named because of their intense staining with 'eosin'. Under the microscope,
eosinophils typically have a bi-lobed nucleus and contain many basic crystal granules in their
cytoplasm. The granules are eosinophil mediators that are toxic to many organisms and also to
tissues. Eosinophils circulate in the blood and emigrate into tissues, are phagocytic, and have been
linked with anti-parasite immunity. Recently, eosinophils have been suggested to play a major role
in the lung pathology associated with the late phase of asthma. There is also some evidence that
they may be involved in immune responses against breast and colon tumors.
Mast Cells
Mast cells are formed in the tissue from undifferentiated precursor cells released into the blood
from the bone marrow. They are not the tissue counterparts of basophils but they are similar in
many respects. Mast cells contain numerous granules with preformed mediators which can be
released from mast cells after stimulation. The preformed mediators include histamine and other
active substances, including some cytokines (such TNF-a).
Stimulation of mast cells also results in the production of newly formed mediators such as
prostaglandins and leukotrienes. Stimulation of mast cells occurs in several ways such as by the
anaphylatoxins (C3a and C5a) of the Complement system or by the cross-linking of surface
IgE. Mast cells have high affinity Fc receptors for the IgE that is produced against an allergen. As
a result, mast cell release is most significant in either acute inflammation or in allergic responses.
Basophils
Basophils are found in low numbers in the blood. Their functions are not well understood but they
are known to be involved in Type I hypersensitivity (allergic) responses. These cells have high
affinity Fc receptors for IgE on their surface. Cross-linking of the IgE causes the basophils to
release pharmacologically active mediators such as heparin and histamine. Basophils, therefore, act
very much like mast cells except that they are in the blood instead of the tissues.
CD4+ Lymphocyte plays a central role in the immune system, which has been linked to that of the
conductor of an orchestra.
A Typical Cell – Structures and Function
The cell is the functional basic unit of life. It was discovered by Robert Hooke and is the functional
unit of all known living organisms. It is the smallest unit of life that is classified as a living thing,
and is often called the building block of life. Some organisms, such as most bacteria, are unicellular
(consist of a single cell). Other organisms, such as humans, are multicellular. (Humans have about
100 trillion or 1014 cells; a typical cell size is 10 µm; a typical cell mass is 1 nanogram. The largest
cells are about 135 µm in the anterior horn in the spinal cord while granule cells in the cerebellum,
the smallest, can be some 4 µm and the longest cell can reach from the toe to the lower brain stem
(Pseudounipolar cells).) The largest known cells are unfertilised ostrich egg cells which weigh 3.3
pounds.
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In 1835, before the final cell theory was developed, Jan Evangelista Purkyně observed small
"granules" while looking at the plant tissue through a microscope. The cell theory, first developed
in 1839 by Matthias Jakob Schleiden and Theodor Schwann, states that all organisms are composed
of one or more cells, that all cells come from preexisting cells, that vital functions of an organism
occur within cells, and that all cells contain the hereditary information necessary for regulating cell
unctions and for transmitting information to the next generation of cells.
The word cell comes from the Latin cellula, meaning, a small room. The descriptive term for the
smallest living biological structure was coined by Robert Hooke in a book he published in 1665
when he compared the cork cells he saw through his microscope to the small rooms monks lived in.
Anatomy of cells
There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually independent,
while eukaryotic cells are often found in multicellular organisms.
Prokaryotic cells
The prokaryote cell is simpler, and therefore smaller, than a eukaryote cell, lacking a nucleus and
most of the other organelles of eukaryotes. There are two kinds of prokaryotes: bacteria and archaea;
these share a similar structure.
A prokaryotic cell has three architectural regions:
* On the outside, flagella and pili project from the cell's surface. These are structures (not present
in all prokaryotes) made of proteins that facilitate movement and communication between cells;
* Enclosing the cell is the cell envelope – generally consisting of a cell wall covering a plasma
membrane though some bacteria also have a further covering layer called a capsule. The envelope
gives rigidity to the cell and separates the interior of the cell from its environment, serving as a
protective filter. Though most prokaryotes have a cell wall, there are exceptions such as
Mycoplasma (bacteria) and Thermoplasma (archaea). The cell wall consists of peptidoglycan in
bacteria, and acts as an additional barrier against exterior forces. It also prevents the cell from
expanding and finally bursting (cytolysis) from osmotic pressure against a hypotonic environment.
Some eukaryote cells (plant cells and fungi cells) also have a cell wall;
* Inside the cell is the cytoplasmic region that contains the cell genome (DNA) and ribosomes and
various sorts of inclusions. A prokaryotic chromosome is usually a circular molecule (an exception
is that of the bacterium Borrelia burgdorferi, which causes Lyme disease). Though not forming a
nucleus, the DNA is condensed in a nucleoid. Prokaryotes can carry extrachromosomal DNA
elements called plasmids, which are usually circular. Plasmids enable additional functions, such as
antibiotic resistance.
Eukaryotic cells
Organelles:
(1) nucleolus
(2) nucleus
(3) ribosome
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(4) vesicle
(5) rough endoplasmic reticulum (ER)
(6) Golgi apparatus
(7) Cytoskeleton
(8) smooth
endoplasmic reticulum
(9) mitochondria
(10) vacuole
(11) cytoplasm
(12) lysosome
(13) centrioles within centrosome
Eukaryotic cells are about 15 times wider than a typical prokaryote and can be as much as 1000
times greater in volume. The major difference between prokaryotes and eukaryotes is that eukaryotic
cells contain membrane-bound compartments in which specific metabolic activities take place. Most
important among these is a cell nucleus, a membrane-delineated compartment that houses the
eukaryotic cell's DNA. This nucleus gives the eukaryote its name, which means "true nucleus."
Other differences include:
* The plasma membrane resembles that of prokaryotes in function, with minor differences in the
setup. Cell walls may or may not be present.
* The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which
are associated with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated
from the cytoplasm by a membrane. Some eukaryotic organelles such as mitochondria also contain
some DNA.
* Many eukaryotic cells are ciliated with primary cilia. Primary cilia play important roles in
chemosensation, mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory
cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling
the signaling to ciliary motility or alternatively to cell division and differentiation."
* Eukaryotes can move using motile cilia or flagella. The flagella are more complex than those of
prokaryotes.
Subcellular components
All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates its
interior from its environment, regulates what moves in and out (selectively permeable), and
maintains the electric potential of the cell. Inside the membrane, a salty cytoplasm takes up most of
the cell volume. All cells possess DNA, the hereditary material of genes, and RNA, containing the
information necessary to build various proteins such as enzymes, the cell's primary machinery. There
are also other kinds of biomolecules in cells. This article will list these primary components of the
cell, then briefly describe their function.
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Cell membrane: A cell's defining boundary
The cytoplasm of a cell is surrounded by a cell membrane or plasma membrane. The plasma
membrane in plants and prokaryotes is usually covered by a cell wall. This membrane serves to
separate and protect a cell from its surrounding environment and is made mostly from a double layer
of lipids (hydrophobic fat-like molecules) and hydrophilic phosphorus molecules. Hence, the layer is
called a phospholipid bilayer. It may also be called a fluid mosaic membrane. Embedded within this
membrane is a variety of protein molecules that act as channels and pumps that move different
molecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can either
let a substance (molecule or ion) pass through freely, pass through to a limited extent or not pass
through at all. Cell surface membranes also contain receptor proteins that allow cells to detect
external signaling molecules such as hormones.
Cytoskeleton: A cell's scaffold
The cytoskeleton acts to organize and maintain the cell's shape; anchors organelles in place; helps
during endocytosis, the uptake of external materials by a cell, and cytokinesis, the separation of
daughter cells after cell division; and moves parts of the cell in processes of growth and mobility.
The eukaryotic cytoskeleton is composed of microfilaments, intermediate filaments and
microtubules. There is a great number of proteins associated with them, each controlling a cell's
structure by directing, bundling, and aligning filaments. The prokaryotic cytoskeleton is less wellstudied but is involved in the maintenance of cell shape, polarity and cytokinesis.
Genetic material
Two different kinds of genetic material exist: deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Most organisms use DNA for their long-term information storage, but some viruses (e.g.,
retroviruses) have RNA as their genetic material. The biological information contained in an
organism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g.,
mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic
code itself. Transfer RNA (tRNA) molecules are used to add amino acids during protein translation.
Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial
chromosome) in the nucleoid region of the cytoplasm. Eukaryotic genetic material is divided into
different, linear molecules called chromosomes inside a discrete nucleus, usually with additional
genetic material in some organelles like mitochondria and chloroplasts (see endosymbiotic theory).
A human cell has genetic material contained in the cell nucleus (the nuclear genome) and in the
mitochondria (the mitochondrial genome). In humans the nuclear genome is divided into 23 pairs of
linear DNA molecules called chromosomes. The mitochondrial genome is a circular DNA molecule
distinct from the nuclear DNA. Although the mitochondrial DNA is very small compared to nuclear
chromosomes, it codes for 13 proteins involved in mitochondrial energy production and specific
tRNAs.
Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a
process called transfection. This can be transient, if the DNA is not inserted into the cell's genome,
or stable, if it is. Certain viruses also insert their genetic material into the genome.
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Organelles
The human body contains many different organs, such as the heart, lung, and kidney, with each
organ performing a different function. Cells also have a set of "little organs," called organelles, that
are adapted and/or specialized for carrying out one or more vital functions.
There are several types of organelles within an animal cell. Some (such as the nucleus and golgi
apparatus) are typically solitary, while others (such as mitochondria, peroxisomes and lysosomes)
can be numerous (hundreds to thousands). The cytosol is the gelatinous fluid that fills the cell and
surrounds the organelles.
Cell nucleus – a cell's information center
The cell nucleus is the most conspicuous organelle found in a eukaryotic cell. It houses the cell's
chromosomes, and is the place where almost all DNA replication and RNA synthesis (transcription)
occur. The nucleus is spherical and separated from the cytoplasm by a double membrane called the
nuclear envelope. The nuclear envelope isolates and protects a cell's DNA from various molecules
that could accidentally damage its structure or interfere with its processing. During processing, DNA
is transcribed, or copied into a special RNA, called messenger RNA (mRNA). This mRNA is then
transported out of the nucleus, where it is translated into a specific protein molecule. The nucleolus
is a specialized region within the nucleus where ribosome subunits are assembled. In prokaryotes,
DNA processing takes place in the cytoplasm.
Mitochondria and Chloroplasts – the power generators
Mitochondria are self-replicating organelles that occur in various numbers, shapes, and sizes in
the cytoplasm of all eukaryotic cells. Mitochondria play a critical role in generating energy in the
eukaryotic cell. Mitochondria generate the cell's energy by oxidative phosphorylation, using oxygen
to release energy stored in cellular nutrients (typically pertaining to glucose) to generate ATP.
Mitochondria multiply by splitting in two. Respiration occurs in the cell mitochondria.
Organelles that are modified chloroplasts are broadly called plastids, and are involved in energy
storage through photosynthesis, which uses solar energy to generate carbohydrates and oxygen from
carbon dioxide and water.
Mitochondria and chloroplasts each contain their own genome, which is separate and distinct from
the nuclear genome of a cell. Both organelles contain this DNA in circular plasmids, much like
prokaryotic cells, strongly supporting the evolutionary theory of endosymbiosis; since these
organelles contain their own genomes and have other similarities to prokaryotes, they are thought to
have developed through a symbiotic relationship after being engulfed by a primitive cell.
Endoplasmic reticulum – eukaryotes only
The endoplasmic reticulum (ER) is the transport network for molecules targeted for certain
modifications and specific destinations, as compared to molecules that will float freely in the
cytoplasm. The ER has two forms: the rough ER, which has ribosomes on its surface and secretes
proteins into the cytoplasm, and the smooth ER, which lacks them. Smooth ER plays a role in
calcium sequestration and release.
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Golgi apparatus – eukaryotes only
The primary function of the Golgi apparatus is to process and package the macromolecules such
as proteins and lipids that are synthesized by the cell. It is particularly important in the processing of
proteins for secretion. The Golgi apparatus forms a part of the endomembrane system of eukaryotic
cells. Vesicles that enter the Golgi apparatus are processed in a cis to trans direction, meaning they
coalesce on the cis side of the apparatus and after processing pinch off on the opposite (trans) side to
form a new vesicle in the animal cell.
Ribosomes
The ribosome is a large complex of RNA and protein molecules. They each consist of two subunits,
and act as an assembly line where RNA from the nucleus is used to synthesise proteins from amino
acids. Ribosomes can be found either floating freely or bound to a membrane (the rough
endoplasmatic reticulum in eukaryotes, or the cell membrane in prokaryotes).
Lysosomes and Peroxisomes – eukaryotes only
Lysosomes contain digestive enzymes (acid hydrolases). They digest excess or worn-out
organelles, food particles, and engulfed viruses or bacteria. Peroxisomes have enzymes that rid the
cell of toxic peroxides. The cell could not house these destructive enzymes if they were not
contained in a membrane-bound system. These organelles are often called a "suicide bag" because
of their ability to detonate and destroy the cell.
Centrosome – the cytoskeleton organizer
The centrosome produces the microtubules of a cell – a key component of the cytoskeleton. It
directs the transport through the ER and the Golgi apparatus. Centrosomes are composed of two
centrioles, which separate during cell division and help in the formation of the mitotic spindle. A
single centrosome is present in the animal cells. They are also found in some fungi and algae cells.
Vacuoles
Vacuoles store food and waste. Some vacuoles store extra water. They are often described as
liquid filled space and are surrounded by a membrane. Some cells, most notably Amoeba, have
contractile vacuoles, which can pump water out of the cell if there is too much water.Thevacuolesof
eukaryotic cells are usually larger in those of plants than animals.
Structures outside the cell wall
Capsule
A gelatinous capsule is present in some bacteria outside the cell wall. The capsule may be
polysaccharide as in pneumococci, meningococci or polypeptide as Bacillus anthracis or hyaluronic
acid as in streptococci.[citation needed] Capsules are not marked by ordinary stain and can be
detected by special stain. The capsule is antigenic. The capsule has antiphagocytic function so it
determines the virulence of many bacteria. It also plays a role in attachment of the organism to
mucous membranes.
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Flagella
Flagella are the organelles of cellular mobility. They arise from cytoplasm and extrude through the
cell wall. They are long and thick thread-like appendages, protein in nature. Are most commonly
found in bacteria cells but are found in animal cells as well.
Fimbriae (pili)
They are short and thin hair like filaments, formed of protein called pilin (antigenic). Fimbriae are
responsible for attachment of bacteria to specific receptors of human cell (adherence). There are
special types of pili called (sex pili) involved in conjunction.
Cell functions
Cell growth and metabolism
Between successive cell divisions, cells grow through the functioning of cellular metabolism. Cell
metabolism is the process by which individual cells process nutrient molecules. Metabolism has
two distinct divisions: catabolism, in which the cell breaks down complex molecules to produce
energy and reducing power, and anabolism, in which the cell uses energy and reducing power to
construct complex molecules and perform other biological functions. Complex sugars consumed by
the organism can be broken down into a less chemically complex sugar molecule called glucose.
Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of
energy, through two different pathways.
The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each
reaction is designed to produce some hydrogen ions that can then be used to make energy packets
(ATP). In prokaryotes, glycolysis is the only method used for converting energy.
The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and
can generate enough ATP to run all the cell functions.
Creation of new cells
Cell division involves a single cell (called a mother cell) dividing into two daughter cells. This
leads to growth in multicellular organisms (the growth of tissue) and to procreation (vegetative
reproduction) in unicellular organisms.
Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of nuclear
division, called mitosis, followed by division of the cell, called cytokinesis. A diploid cell may also
undergo meiosis to produce haploid cells, usually four. Haploid cells serve as gametes in
multicellular organisms, fusing to form new diploid cells.
DNA replication, or the process of duplicating a cell's genome, is required every time a cell divides.
Replication, like all cellular activities, requires specialized proteins for carrying out the job.
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Protein synthesis
Cells are capable of synthesizing new proteins, which are essential for the modulation and
maintenance of cellular activities. This process involves the formation of new protein molecules
from amino acid building blocks based on information encoded in DNA/RNA. Protein synthesis
generally consists of two major steps: transcription and translation.
Transcription is the process where genetic information in DNA is used to produce a complementary
RNA strand. This RNA strand is then processed to give messenger RNA (mRNA), which is free to
migrate through the cell. mRNA molecules bind to protein-RNA complexes called ribosomes
located in the cytosol, where they are translated into polypeptide sequences. The ribosome mediates
the formation of a polypeptide sequence based on the mRNA sequence. The mRNA sequence
directly relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter molecules
in binding pockets within the ribosome. The new polypeptide then folds into a functional threedimensional protein molecule.
Cell movement or motility
Cells can move during many processes: such as wound healing, the immune response and cancer
metastasis. For wound healing to occur, white blood cells and cells that ingest bacteria move to the
wound site to kill the microorganisms that cause infection.
At the same time fibroblasts (connective tissue cells) move there to remodel damaged structures. In
the case of tumor development, cells from a primary tumor move away and spread to other parts of
the body. Cell motility involves many receptors, crosslinking, bundling, binding, adhesion, motor
and other proteins.
The process is divided into three steps – protrusion of the leading edge of the cell, adhesion of the
leading edge and de-adhesion at the cell body and rear, and cytoskeletal contraction to pull the cell
forward. Each step is driven by physical forces generated by unique segments of the cytoskeleton.
Evolution
The origin of cells has to do with the origin of life, which began the history of life on Earth.
Origin of the first cell
There are several theories about the origin of small molecules that could lead to life in an early
Earth. One is that they came from meteorites (see Murchison meteorite). Another is that they were
created at deep-sea vents. A third is that they were synthesized by lightning in a reducing
atmosphere (see Miller–Urey experiment); although it is not clear if Earth had such an atmosphere.
There are essentially no experimental data defining what the first self-replicating forms were. RNA
is generally assumed to be the earliest self-replicating molecule, as it is capable of both storing
genetic information and catalyzing chemical reactions (see RNA world hypothesis). But some other
entity with the potential to self-replicate could have preceded RNA, like clay or peptide nucleic
acid.
Cells emerged at least 4.0–4.3 billion years ago. The current belief is that these cells were
heterotrophs. An important characteristic of cells is the cell membrane, composed of a bilayer of
lipids. The early cell membranes were probably more simple and permeable than modern ones,
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with only a single fatty acid chain per lipid. Lipids are known to spontaneously form bilayered
vesicles in water, and could have preceded RNA. But the first cell membranes could also have been
produced by catalytic RNA, or even have required structural proteins before they could form.
Origin of eukaryotic cells
The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNAbearing organelles like the mitochondria and the chloroplasts are almost certainly what remains of
ancient symbiotic oxygen-breathing proteobacteria and cyanobacteria, respectively, where the rest
of the cell seems to be derived from an ancestral archaean prokaryote cell – a theory termed the
endosymbiotic theory.
There is still considerable debate about whether organelles like the hydrogenosome predated the
origin of mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.
Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant
eukaryotes, may have played a role in the transition from prokaryotes to eukaryotes. An 'origin of
sex as vaccination' theory suggests that the eukaryote genome accreted from prokaryan parasite
genomes in numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose when
infected hosts began swapping nuclearized genomes containing co-evolved, vertically transmitted
symbionts that conveyed protection against horizontal infection by more virulent symbionts.
STRUCTURE AND FUNCTION OF DIFFERENT TISSUES
Epithelial Tissue
Epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout
the body. Many glands are also formed from epithelial tissue. It lies on top of connective tissue, and
the two layers are separated by a basement membrane.
In humans, epithelium is classified as a primary body tissue, the other ones being connective tissue,
muscle tissue and nervous tissue.
Epithelium is often defined by the expression of the adhesion molecule e-cadherin (as opposed to ncadherin, which is used by cells of the connective tissue).
Functions of epithelial cells include secretion, selective absorption, protection, transcellular
transport and detection of sensation. As a result, they commonly present extensive apicalbasolateral polarity (e.g. different membrane proteins expressed) and specialization.
General characters of epithelial tissue

It may develop from ectoderm , mesoderm ,or endoderm.

The epithelial cells rest on a basement membrane which may be clear or not clear.

No blood vessels can enter in between epithelial cells but nerves can , so epithelial tissue is
avascular tissue.

Epithelial tissue receives nutrition by diffusion from the underlying connective tissue.
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Classification (structural)
Epithelial tissue can be structurally divided into two groups depending on the number of layers of
which it is composed. Epithelial tissue that is only one cell thick is known as simple epithelium. If
it is two or more cells thick, it is known as stratified epithelium.
However, when taller simple epithelial cells (see columnar, below) are viewed in cross section with
several nuclei appearing at different heights, they can be confused with stratified epithelia. This
kind of epithelium is therefore described as "pseudostratified" epithelium.
Regardless of the type, any epithelium is separated from the underlying tissue by a thin layer of
connective tissue known as the basement membrane. The basement membrane provides structural
support for the epithelium and also binds it to neighbouring structures.
Simple epithelium
Simple epithelium is one cell thick; that is, every cell is in contact with the underlying basement
membrane. Simple epithelium can be subdivided further according to the shape and function of its
cells.
Stratified Epithelium
Stratified epithelium differs from simple epithelium in that it is multilayered. It is therefore found
where body linings have to withstand mechanical or chemical insult such that layers can be abraded
and lost without exposing subepithelial layers. Cells flatten as the layers become more apical,
though in their most basal layers the cells can be squamous, cuboidal or columnar.
Functions
* Protection: Epithelial cells protect underlying tissue from mechanical injury, harmful
chemicals and pathogens and excessive water loss.
* Sensation: Sensory stimuli are detected by specialized epithelial cells. Specialized epithelial
tissue containing sensory nerve endings is found in the skin, eyes, ears and nose and on the tongue.
* Secretion: In glands, epithelial tissue is specialized to secrete specific chemical substances
such as enzymes, hormones and lubricating fluids.
* Absorption: Certain epithelial cells lining the small intestine absorb nutrients from the
digestion of food.
* Excretion: Epithelial tissues in the kidney excrete waste products from the body and reabsorb
needed materials from the urine. Sweat is also excreted from the body by epithelial cells in the
sweat glands.
* Diffusion: Simple epithelium promotes the diffusion of gases, liquids and nutrients. Because
they form such a thin lining, they are ideal for the diffusion of gases (e.g. walls of capillaries and
lungs).
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Location
Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermost
layer of our skin is composed of dead stratified squamous, keratinized epithelial cells.
Tissues that line the inside of the mouth, the oesophagus and part of the rectum are composed of
nonkeratinized stratified squamous epithelium. Other surfaces that separate body cavities from the
outside environment are lined by simple squamous, columnar, or pseudostratified epithelial cells.
Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive and
urinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea is
covered with fast-growing, easily-regenerated epithelial cells. Endothelium (the inner lining of
blood vessels, the heart, and lymphatic vessels) is a specialized form of epithelium. Another type,
mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.
Cell junctions
A cell junction is a structure within a tissue of a multicellular organism. Cell junctions are
especially abundant in epithelial tissues. They consist of protein complexes and provide contact
between neighbouring cells, between a cell and the extracellular matrix, or they built up the
paracellular barrier of epithelia and control the paracellular transport.
Secretory epithelia
As stated above, secretion is one major function of epithelial cells. Glands are formed from the
invagination / infolding of epithelial cells and subsequent growth in the underlying connective
tissue. There are two major classifications of glands: endocrine glands and exocrine glands.
Endocrine glands are glands that secrete their product directly onto a surface rather than through a
duct. This group contains the glands of the Endocrine system.
Sensing the extracellular environment
"Some epithelial cells are ciliated, and they commonly exist as a sheet of polarised cells forming a
tube or tubule with cilia projecting into the lumen." Primary cilia on epithelial cells provide
chemosensation, thermosensation and mechanosensation of the extracellular environment by
playing "a sensory role mediating specific signalling cues, including soluble factors in the external
cell environment, a secretory role in which a soluble protein is released to have an effect
downstream of the fluid flow, and mediation of fluid flow if the cilia are motile."
Embryology
In general, there are epithelial tissues deriving from all of the embryological germ layers:
* from ectoderm (e.g., the epidermis);
* from endoderm (e.g., the lining of the gastrointestinal tract);
* from mesoderm (e.g., the inner linings of body cavities).
However, it is important to note that pathologists do not consider endothelium and mesothelium
(both derived from mesoderm) to be true epithelium. This is because such tissues present very
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different pathology. For that reason, pathologists label cancers in endothelium and mesothelium
sarcomas, whereas true epithelial cancers are called carcinomas. Also, the filaments that support
these mesoderm-derived tissues are very distinct. Outside of the field of pathology, it is, in general,
accepted that the epithelium arises from all three germ layers.
Connective tissue
Connective tissue is a form of fibrous tissue.. It is one of the four types of tissue in traditional
classifications (the others being epithelial, muscle, and nervous tissue).
Collagen is the main protein of connective tissue in animals and the most abundant protein in
mammals, making up about 25% of the total protein content.
Fiber types
Fiber types as follows:
* collagenous fibers
* elastic fibers
* Bone Marrow
Disorders of connective tissue
Various connective tissue conditions have been identified; these can be both inherited and
environmental.
* Marfan syndrome - a genetic disease causing abnormal fibrillin.
* Scurvy - caused by a dietary deficiency in vitamin C, leading to abnormal collagen.
* Ehlers-Danlos syndrome - deficient type III collagen- a genetic disease causing progressive
deterioration of collagens, with different EDS types affecting different sites in the body, such as
joints, heart valves, organ walls, arterial walls, etc.
* Loeys-Dietz syndrome - a genetic disease related to Marfan syndrome, with an emphasis on
vascular deterioration.
* Pseudoxanthoma elasticum - an autosomal recessive hereditary disease, caused by calcification
and fragmentation of elastic fibres, affecting the skin, the eyes and the cardiovascular system.
* Systemic lupus erythematosus - a chronic, multisystem, inflammatory disorder of probable
autoimmune etiology, occurring predominantly in young women.
* Osteogenesis imperfecta (brittle bone disease) - caused by insufficient production of good quality
collagen to produce healthy, strong bones.
* Fibrodysplasia ossificans progressiva - disease of the connective tissue, caused by a defective
gene which turns connective tissue into bone.
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* Spontaneous pneumothorax - collapsed lung, believed to be related to subtle abnormalities in
connective tissue.
* Sarcoma - a neoplastic process originating within connective tissue.
Staining of connective tissue
For microscopic viewing, the majority of the connective tissue staining techniques color tissue
fibers in contrasting shades. Collagen may be differentially stained by any of the following
techniques:
 Van Gieson's stain
 Masson's Trichrome stain
 Mallory's Aniline Blue stain
 Azocarmine stain
 Krajian's Aniline Blue stain
Muscular Tissue
Muscular tissue is the basic tissue characterized by the ability to contract upon stimulation.
Muscular tissues are vascularized tissues chiefly composed of elongated cells that are excitable and
contractile, and usually arranged in parallel. In the body, there are three types of muscular tissue:
skeletal muscle, smooth muscle, and cardiac muscle.
Description
Muscular tissue is largely composed of muscle cells. Muscle cells are elongated and surrounded by
external lamina, which is similar to basal lamina of epithelial tissues. Muscle cells contain a
contractile apparatus composed of actin (thin) and myosin (thick) filaments, and associated
proteins. In striated muscle cells, the contractile apparatus is organized into myofibrils, which are
oriented in the same direction as the long axis of the muscle cell. The regular repeating segments
(sacromeres) of myofibrils give skeletal and cardiac muscle cells transverse striations. In smooth
muscle cells, the contractile apparatus, actin and myosin filaments form contractile fibers, which do
not appear as highly organized as myofibrils.
Skeletal Muscle
Skeletal muscle cells, also known as skeletal muscle fibers, are very long, multinucleated syncytial
cells that were formed during development by fusion of myoblast cells. Relative to other muscle
cells, skeletal muscle cells are long and wide.
In cross section, skeletal muscle cells are polygonal in shape, and their nuclei are located
peripherally, adjacent to the plasma membrane (sarcolemma).
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Cardiac Muscle
Cardiac muscle fibers are composed of branching and anastomosing chains of cardiac muscle cells.
Cardiac muscle cells within a fiber are joined to their neighbors by intercalated discs, which contain
anchoring and gap junctions. The anchoring junctions (adherens junctions and desmosomes)
physically connect the cytoskeletons and contractile apparatuses of the neighboring cells. The gap
junctions electrically couple the cells.
In cross section, cardiac muscle cells are rounded in shape, have a single central nucleus, and are
intermediate in size between skeletal and smooth muscle cells.
Smooth Muscle
Smooth muscle is composed of sheets or bundles of relatively short, spindle-shaped cells, in a
staggered array. Smooth muscle cells are not striated, and have a single central nucleus. In some
smooth muscle, the cells are interconnected by gap junctions.
In cross section, smooth muscle cells are circular. Diameters of cross-sectional profiles differ; the
largest profiles display a central nucleus.
Role of Muscular Tissue in the Body
The special role of muscular tissues is contraction, an ability the body puts to multiple uses.

Skeletal muscle makes up the muscles of the muscular system. As part of the
musculoskeletal system, skeletal muscle is involved in body posture and movement.
Skeletal muscle is also found in the extra-ocular muscles, and muscles of the auditory
ossicles, tongue, soft palate and fauces, pharynx, larynx, pelvic diaphragm, and perineum.

Smooth muscle in the walls of hollow visceral organs, ducts, arteries, and veins controls the
movement of contents in the lumen. Some bundles of smooth muscle form sphincters.
Smooth muscle is also found in arrector pili muscles of the skin, and in intrinsic muscles of
the eye.

Cardiac muscle in the walls of the atria and ventricles of the heart pump blood through the
cardiovascular system
Working
Muscle tissue contracts following excitation. Excitation of muscle cells causes an increase in
calcium ion concentration in the cytosol. Calcium ions bind to proteins that regulate the interaction
of actin and myosin filaments, triggering contraction. Muscle tissue types differ in the details of the
excitation and initiation of actin-myosin interactions.
Skeletal muscle
Muscles of the skeletal system are generally considered voluntary muscles, because they can be
subject to conscious control. Muscle contraction may also be subconscious, such as reflex
movements. Muscles are innervated by cranial or spinal nerves.
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Skeletal muscle fibers form neuromuscular junctions with motor neurons, whose cell bodies are
located in the spinal cord or brainstem. A motor unit consists of a motor neuron and the fibers that
it innervates.
Neurotransmission at the neuromuscular junction causes depolarization of the sarcolemma and
transverse tubules. Depolarization releases calcium ions from the sacroplasmic reticulum into the
cytosol, where it binds troponin C, allowing interaction of actin and myosin filaments.
Cardiac muscle
The contraction of cardiac muscle is involuntary, strong, and rhythmical. Cardiac muscle cells have
an intrinsic pacemaker mechanism. Cardiac muscle cells with the highest pacemaker rate determine
the rate of contraction of all cardiac muscle fibers to which they are connected. The rate and force
of contraction can also be modified by hormones and the autonomic nervous system.
Cardiac muscle cells are excited by depolarization through the fiber spread by gap junctions.
Depolarization leads to increased calcium in the cytosol from the extracellular space, as well as
sarcoplasmic reticulum. Actin-myosin interactions are triggered by binding of calcium by troponin
C, as in skeletal muscle.
Smooth muscle
Smooth muscle contraction is involuntary. Physiologically, smooth muscle is often described as
being either multi-unit or unitary. In multi-unit smooth muscle, such as the muscles in the iris, the
cells are not interconnected by gap junctions. These cells are individually controlled by the
autonomic nervous system.
In unitary smooth muscle, the cells are interconnected by gap junctions. Contraction of unitary
smooth muscle, for example, in the walls of the intestines, is often described as slow and rhythmic.
The rate and force of contraction are modulated by the autonomic nervous system and hormones.
Excitation of smooth muscle cells, either by autonomic nerve fibers or through gap junctions,
causes extracellular calcium ions to enter the cytosol. Calmodulin binds calcium ions and activates
myosin light-chain kinase, which phosphorylates a myosin light chain, unmasking myosin's actinbinding site.
Nervous tissue
Nervous tissue is one of four major classes of vertebrate tissue.
Nervous tissue is the main component of the nervous system-the brain, spinal cord, and nerveswhich regulates and controls body functions. It is composed of neurons, which transmit impulses,
and the neuroglialcells, which assist propagation of the nerve impulse as well as provide nutrients
to the neuron.
Nervous tissue is made of nerve cells that come in many varieties, all of which are distinctly
characteristic by the axon or long stem like part of the cell that sends action potential signals to the
next cell.
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Functions of the nervous system are sensory input, integration, controls of muscles and glands,
homeostasis, and mental activity.
All living cells have the ability to react to stimuli. Nervous tissue is specialized to react to stimuli
and to conduct impulses to various organs in the body which bring about a response to the stimulus.
Nerve tissue (as in the brain, spinal cord and peripheral nerves that branch throughout the body) are
all made up of specialized nerve cells called neurons. Neurons are easily stimulated and transmit
impulses very rapidly. A nerve is made up of many nerve cell fibers (neurons) bound together by
connective tissue. A sheath of dense connective tissue, the epineurium surrounds the nerve. This
sheath penetrates the nerve to form the perineurium which surrounds bundles of nerve fibers. Blood
vessels of various sizes can be seen in the epineurium. The endoneurium, which consists of a thin
layer of loose connective tissue, surrounds the individual nerve fibers.
The cell body is enclosed by a cell (plasma) membrane and has a central nucleus. Granules called
Nissl bodies are found in the cytoplasm of the cell body. Within the cell body, extremely fine
neurofibrils extend from the dendrites into the axon. The axon is surrounded by the myelin sheath,
which forms a whitish, non-cellular, fatty layer around the axon. Outside the myelin sheath is a
cellular layer called the neurilemma or sheath of Schwann cells. The myelin sheath together with
the neurilemma is also known as the medullary sheath. This medullary sheath is interrupted at
intervals by the nodes of Ranvier.
Neuronal Communication
Nerve cells are functionally made to each other at a junction known as a synapse, where the
terminal branches of an axon and the dendrites of another neuron lie in close proximity to each
other but normally without direct contact. Information is transmitted across the gap by chemical
secretions called neurotransmitters. It causes activation in the post-synaptic cell.All cells possess
the ability to respond to stimuli. The messages carried by the nervous system are electrical signals
called impulses.
Classification of Neurons
Neurons are classified both structurally and functionally.
Structural Classification Neurons are grouped structurally according to the number of processes
extending from their cell body. Three major neuron groups make up this classification: multipolar
(polar = end, pole), bipolar and unipolar neurons.
Multipolar Neurons (3+ processes)
They are the most common neuron type in humans (more than 99% of neurons belong to this
class) and the major neuron type in the CNS
Bipolar Neurons
Bipolar neurons are spindle-shaped, with a dendrite at one end and an axon at the other . An
example can be found in the light-sensitive retina of the eye.
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Unipolar Neurons
Sensory neurons have only a single process or fibre which divides close to the cell body into two
main branches (axon and dendrite). Because of their structure they are often referred to as unipolar
neurons.
Cancer
Tumors in nervous tissue include:
* Gliomas (glial cell tumors)
Gliomatosis cerebri, Oligoastrocytoma, Choroid plexus papilloma, Ependymoma, Astrocytoma
(Pilocytic astrocytoma, Glioblastoma multiforme), Dysembryoplastic neuroepithelial tumour,
Oligodendroglioma, Medulloblastoma, Primitive neuroectodermal tumor
* Neuroepitheliomatous tumors
Ganglioneuroma, Neuroblastoma, Atypical teratoid rhabdoid tumor, Retinoblastoma,
Esthesioneuroblastoma
* Nerve sheath tumors
Neurofibroma (Neurofibrosarcoma, Neurofibromatosis), Schwannoma, Neurinoma, Acoustic
neuroma, Neuroma
Genes – Structure and Function, How do genes work?
A gene is a unit of heredity in a living organism. It is normally a stretch of DNA that codes for a
type of protein or for an RNA chain that has a function in the organism. All proteins and functional
RNA chains are specified by genes. All living things depend on genes. Genes hold the information
to build and maintain an organism's cells and pass genetic traits to offspring. A modern working
definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of
inheritance, which is associated with regulatory regions, transcribed regions, and or other functional
sequence regions ". Colloquial usage of the term gene (e.g. "good genes, "hair color gene") may
actually refer to an allele: a gene is the basic instruction, a sequence of nucleic acid (DNA or, in the
case of certain viruses RNA), while an allele is one variant of that instruction
The notion of a gene is evolving with the science of genetics, which began when Gregor Mendel
noticed that biological variations are inherited from parent organisms as specific, discrete traits.
The biological entity responsible for defining traits was later termed a gene, but the biological basis
for inheritance remained unknown until DNA was identified as the genetic material in the 1940s.
All organisms have many genes corresponding to many different biological traits, some of which
are immediately visible, such as eye color or number of limbs, and some of which are not, such as
blood type or increased risk for specific diseases, or the thousands of basic biochemical processes
that comprise life.
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The vast majority of living organisms encode their genes in long strands of DNA. DNA
(deoxyribonucleic acid) consists of a chain made from four types of nucleotide subunits, each
composed of: a five-carbon sugar (2'-deoxyribose), a phosphate group, and one of the four bases
adenine, cytosine, guanine, and thymine. The most common form of DNA in a cell is in a double
helix structure, in which two individual DNA strands twist around each other in a right-handed
spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine
pairs with thymine. The base pairing between guanine and cytosine forms three hydrogen bonds,
whereas the base pairing between adenine and thymine forms two hydrogen bonds. The two strands
in a double helix must therefore be complementary, that is, their bases must align such that the
adenines of one strand are paired with the thymines of the other strand, and so on.
Due to the chemical composition of the pentose residues of the bases, DNA strands have
directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose;
this is known as the 3' end of the molecule. The other end contains an exposed phosphate group;
this is the 5' end. The directionality of DNA is vitally important to many cellular processes, since
double helices are necessarily directional (a strand running 5'-3' pairs with a complementary strand
running 3'-5'), and processes such as DNA replication occur in only one direction. All nucleic acid
synthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydration
reaction that uses the exposed 3' hydroxyl as a nucleophile.
The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type
of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather
than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less
stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a
series of three-nucleotide sequences called codons, which serve as the words in the genetic
language. The genetic code specifies the correspondence during protein translation between codons
and amino acids. The genetic code is nearly the same for all known organisms.
RNA genes and genomes
When proteins are manufactured, the gene is first copied into RNA as an intermediate product. In
other cases, the RNA molecules are the actual functional products. For example, RNAs known as
ribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNA
sequences from which such RNAs are transcribed are known as RNA genes.
Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because
they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are
infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses,
such as HIV, require the reverse transcription of their genome from RNA into DNA before their
proteins can be synthesized. In 2006, French researchers came across a puzzling example of RNAmediated inheritance in mouse. Mice with a loss-of-function mutation in the gene Kit have white
tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The
research team traced this effect back to mutated Kit RNA.[4] While RNA is common as genetic
storage material in viruses, in mammals in particular RNA inheritance has been observed very
rarely.
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Functional structure of a gene
All genes have regulatory regions in addition to regions that explicitly code for a protein or RNA
product. A regulatory region shared by almost all genes is known as the promoter, which provides a
position that is recognized by the transcription machinery when a gene is about to be transcribed
and expressed. A gene can have more than one promoter, resulting in RNAs that differ in how far
they extend in the 5' end. Although promoter regions have a consensus sequence that is the most
common sequence at this position, some genes have "strong" promoters that bind the transcription
machinery well, and others have "weak" promoters that bind poorly. These weak promoters usually
permit a lower rate of transcription than the strong promoters, because the transcription machinery
binds to them and initiates transcription less frequently. Other possible regulatory regions include
enhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream"—
that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regions
are much more complex and difficult to identify than prokaryotic promoters.
Many prokaryotic genes are organized into operons, or groups of genes whose products have
related functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribed
only one at a time, but may include long stretches of DNA called introns which are transcribed but
never translated into protein (they are spliced out before translation). Splicing can also occur in
prokaryotic genes, but is less common than in eukaryotes.
Chromosomes
The total complement of genes in an organism or cell is known as its genome, which may be stored
on one or more chromosomes; the region of the chromosome at which a particular gene is located is
called its locus. A chromosome consists of a single, very long DNA helix on which thousands of
genes are encoded. Prokaryotes—bacteria and archaea—typically store their genomes on a single
large, circular chromosome, sometimes supplemented by additional small circles of DNA called
plasmids, which usually encode only a few genes and are easily transferable between individuals.
For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can
be passed between individual cells, even those of different species, via horizontal gene transfer.
Although some simple eukaryotes also possess plasmids with small numbers of genes, the majority
of eukaryotic genes are stored on multiple linear chromosomes, which are packed within the
nucleus in complex with storage proteins called histones. The manner in which DNA is stored on
the histone, as well as chemical modifications of the histone itself, are regulatory mechanisms
governing whether a particular region of DNA is accessible for gene expression. The ends of
eukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres,
which do not code for any gene product but are present to prevent degradation of coding and
regulatory regions during DNA replication. The length of the telomeres tends to decrease each time
the genome is replicated in preparation for cell division; the loss of telomeres has been proposed as
an explanation for cellular senescence, or the loss of the ability to divide, and by extension for the
aging process in organisms.
Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often
contain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple singlecelled eukaryotes have relatively small amounts of such DNA, whereas the genomes of complex
multicellular organisms, including humans, contain an absolute majority of DNA without an
identified function.[8] However it now appears that, although protein-coding DNA makes up barely
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2% of the human genome, about 80% of the bases in the genome may be being expressed, so the
term "junk DNA" may be a misnomer.
Gene expression
In all organisms, there are two major steps separating a protein-coding gene from its protein: First,
the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA);
and, second, it must be translated from mRNA to protein. RNA-coding genes must still go through
the first step, but are not translated into protein. The process of producing a biologically functional
molecule of either RNA or protein is called gene expression, and the resulting molecule itself is
called a gene product.
Genetic code
The genetic code is the set of rules by which a gene is translated into a functional protein. Each
gene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA) strand;
a correspondence between nucleotides, the basic building blocks of genetic material, and amino
acids, the basic building blocks of proteins, must be established for genes to be successfully
translated into functional proteins. Sets of three nucleotides, known as codons, each correspond to a
specific amino acid or to a signal; three codons are known as "stop codons" and, instead of
specifying a new amino acid, alert the translation machinery that the end of the gene has been
reached. There are 64 possible codons (four possible nucleotides at each of three positions, hence
43 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple
codons can specify the same amino acid. The correspondence between codons and amino acids is
nearly universal among all known living organisms.
Transcription
The process of genetic transcription produces a single-stranded RNA molecule known as
messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was
transcribed. The DNA strand whose sequence matches that of the RNA is known as the coding
strand and the strand from which the RNA was synthesized is the template strand. Transcription is
performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5'
direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first
recognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation is
the blocking or sequestering of the promoter region, either by tight binding by repressor molecules
that physically block the polymerase, or by organizing the DNA so that the promoter region is not
accessible.
In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may
begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes,
transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNA
molecule produced by the polymerase is known as the primary transcript and must undergo posttranscriptional modifications before being exported to the cytoplasm for translation. The splicing of
introns present within the transcribed region is a modification unique to eukaryotes; alternative
splicing mechanisms can result in mature transcripts from the same gene having different sequences
and thus coding for different proteins. This is a major form of regulation in eukaryotic cells.
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Translation
Translation is the process by which a mature mRNA molecule is used as a template for
synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and
protein responsible for carrying out the chemical reactions to add new amino acids to a growing
polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a
time, in units called codons, via interactions with specialized RNA molecules called transfer RNA
(tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to
the codon it reads; the tRNA is also covalently attached to the amino acid specified by the
complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the
ribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized from
amino terminus to carboxyl terminus. During and after its synthesis, the new protein must fold to its
active three-dimensional structure before it can carry out its cellular function.
DNA replication and inheritance
The growth, development, and reproduction of organisms relies on cell division, or the process by
which a single cell divides into two usually identical daughter cells. This requires first making a
duplicate copy of every gene in the genome in a process called DNA replication. The copies are
made by specialized enzymes known as DNA polymerases, which "read" one strand of the doublehelical DNA, known as the template strand, and synthesize a new complementary strand. Because
the DNA double helix is held together by base pairing, the sequence of one strand completely
specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to
produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of
the genome inherited by each daughter cell contains one original and one newly synthesized strand
of DNA.
After DNA replication is complete, the cell must physically separate the two copies of the genome
and divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - this
usually occurs via a relatively simple process called binary fission, in which each circular genome
attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates
to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast
compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex
process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S
phase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs during
M phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common,
which results in asymmetrical portions of cytoplasm in the two daughter cells.
Molecular inheritance
The duplication and transmission of genetic material from one generation of cells to the next is the
basis for molecular inheritance, and the link between the classical and molecular pictures of genes.
Organisms inherit the characteristics of their parents because the cells of the offspring contain
copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be
a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized
form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or
contain only one copy of each gene. The gametes produced by females are called eggs or ova, and
those produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell
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that once again has a diploid number of genes—each with one copy from the mother and one copy
from the father.
During the process of meiotic cell division, an event called genetic recombination or crossing-over
can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of
DNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids are
the same, but results in reassortment of otherwise linked alleles if they are different. The Mendelian
principle of independent assortment asserts that each of a parent's two genes for each trait will sort
independently into gametes; which allele an organism inherits for one trait is unrelated to which
allele it inherits for another trait. This is in fact only true for genes that do not reside on the same
chromosome, or are located very far from one another on the same chromosome. The closer two
genes lie on the same chromosome, the more closely they will be associated in gametes and the
more often they will appear together; genes that are very close are essentially never separated
because it is extremely unlikely that a crossover point will occur between them. This is known as
genetic linkage.
History
Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which
proposes that the traits of the parents blend or mix in a smooth, continuous gradient in the
offspring. Although Mendel's work was largely unrecognized after its first publication in 1866, it
was rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von
Tschermak, who had reached similar conclusions from their own research. However, these
scientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.
The existence of genes was first suggested by Gregor Mendel (1822–1884), who, in the 1860s,
studied inheritance in peaplants (Pisum sativum) and hypothesized a factor that conveys traits from
parent to offspring. He spent over 10 years of his life on one experiment. Although he did not use
the term gene, he explained his results in terms of inherited characteristics. Mendel was also the
first to hypothesize independent assortment, the distinction between dominant and recessive traits,
the distinction between a heterozygote and homozygote, and the difference between what would
later be described as genotype (the genetic material of an organism) and phenotype (the visible
traits of that organism). Mendel's concept was given a name by Hugo de Vries in 1889, who, at that
time probably unaware of Mendel's work, in his book Intracellular Pangenesis coined the term
"pangen" for "the smallest particle [representing] one hereditary characteristic".
Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would later
become known as Chromosomes had been observed separating out during cell division by Wilhelm
Hofmeister as early as 1848. The idea that chromosomes are the carriers of inheritance was
expressed in 1883 by Wilhelm Roux. The modern conception of the gene originated with work by
Gregor Mendel, a 19th-century Augustinian monk who systematically studied heredity in pea
plants. Mendel's work was the first to illustrate particulate inheritance, or the theory that inherited
traits are passed from one generation to the next in discrete units that interact in well-defined ways.
Danish botanist Wilhelm Johannsen coined the word "gene" ("gen" in Danish and German) in 1909
to describe these fundamental physical and functional units of heredity, while the related word
genetics was first used by William Bateson in 1905.The word was derived from Hugo de Vries'
1889 term pangen for the same concept, itself a derivative of the word pangenesis coined by
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Darwin (1868). The word pangenesis is made from the Greek words pan (a prefix meaning
"whole", "encompassing") and genesis ("birth") or genos ("origin").
In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, Thomas
Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes
occupy specific locations on the chromosome. With this knowledge, Morgan and his students began
the first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed that
genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse
of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe
strain of the same bacteria, killing the mouse.
A series of subsequent discoveries led to the realization decades later that chromosomes within
cells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), a
polymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance are
encoded.
In 1941, George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused
errors in specific steps in metabolic pathways. This showed that specific genes code for specific
proteins, leading to the "one gene, one enzyme" hypothesis. Oswald Avery, Colin Munro MacLeod,
and Maclyn McCarty showed in 1944 that DNA holds the gene's information. In 1953, James D.
Watson and Francis Crick demonstrated the molecular structure of DNA. Together, these
discoveries established the central dogma of molecular biology, which states that proteins are
translated from RNA which is transcribed from DNA. This dogma has since been shown to have
exceptions, such as reverse transcription in retroviruses.
In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of
Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for
Bacteriophage MS2 coat protein.Richard J. Roberts and Phillip Sharp discovered in 1977 that genes
can be split into segments. This led to the idea that one gene can make several proteins. Recently
(as of 2003–2006), biological results let the notion of gene appear more slippery. In particular,
genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNA
producing distinct proteins may overlap, so that the idea emerges that "genes are one long
continuum".
It was first hypothesized in 1986 by Walter Gilbert that neither DNA nor protein would be required
in such a primitive system as that of a very early stage of the earth if RNA could perform as simply
a catalyst and genetic information storage processor.
The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis
of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary
synthesis.
Mendelian inheritance and classical genetics
According to the theory of Mendelian inheritance, variations in phenotype—the observable
physical and behavioral characteristics of an organism—are due to variations in genotype, or the
organism's particular set of genes, each of which specifies a particular trait. Different forms of a
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gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the pea
plants Mendel worked on, along with many plants and animals, have two alleles for each trait, one
inherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to their
corresponding phenotypes when paired with any other allele for the same trait, whereas recessive
alleles give rise to their corresponding phenotype only when paired with another copy of the same
allele. For example, if the allele specifying tall stems in pea plants is dominant over the allele
specifying short stems, then pea plants that inherit one tall allele from one parent and one short
allele from the other parent will also have tall stems. Mendel's work found that alleles assort
independently in the production of gametes, or germ cells, ensuring variation in the next generation.
Mutation
DNA replication is for the most part extremely accurate, with an error rate per site of around 10−6
to 10−10 in eukaryotes.[9] Rare, spontaneous alterations in the base sequence of a particular gene
arise from a number of sources, such as errors in DNA replication and the aftermath of DNA
damage. These errors are called mutations. The cell contains many DNA repair mechanisms for
preventing mutations and maintaining the integrity of the genome; however, in some cases—such
as breaks in both DNA strands of a chromosome — repairing the physical damage to the molecule
is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some
mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of
the protein for which they code; for example, the codons UCU and UUC both code for serine, so
the U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are most
often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's
fitness.
Mutations propagated to the next generation lead to variations within a species' population.
Variants of a single gene are known as alleles, and differences in alleles may give rise to
differences in traits. Although it is rare for the variants in a single gene to have clearly
distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic
loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants.
However, this does not imply that the wild-type allele is the ancestor from which the mutants are
descended.
Genome
Chromosomal organization
The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the
vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes
usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes
called chromosomes. Genes that appear together on one chromosome of one species may appear on
separate chromosomes in another species. Many species carry more than one copy of their genome
within each of their somatic cells. Cells or organisms with only one copy of each chromosome are
called haploid; those with two copies are called diploid; and those with more than two copies are
called polyploid. The copies of genes on the chromosomes are not necessarily identical. In sexually
reproducing organisms, one copy is normally inherited from each parent.
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Number of genes
Early estimates of the number of human genes that used expressed sequence tag data put it at 50
000–100 000. Following the sequencing of the human genome and other genomes, it has been
found that rather few genes (~20 000 in human, mouse and fly, ~13 000 in roundworm, >46 000 in
rice) encode all the proteins in an organism. These protein-coding sequences make up 1–2% of the
human genome.[18] A large part of the genome is transcribed however, to introns, retrotransposons
and seemingly a large array of noncoding RNAs.
Genetic and genomic nomenclature
Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC)
for each known human gene in the form of an approved gene name and symbol (short-form
abbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique and
each gene is only given one approved gene symbol. It is necessary to provide a unique symbol for
each gene so that people can talk about them. This also facilitates electronic data retrieval from
publications. In preference each symbol maintains parallel construction in different members of a
gene family and can be used in other species, especially the mouse.
Evolutionary concept of a gene
George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book
Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when
we are talking about natural selection favoring some genes. The definition is: "that which
segregates and recombines with appreciable frequency." According to this definition, even an
asexual genome could be considered a gene, insofar that it have an appreciable permanency through
many generations.
The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a
unit.
Richard Dawkins' books The Selfish Gene (1976) and The Extended Phenotype (1982) defended
the idea that the gene is the only replicator in living systems. This means that only genes transmit
their structure largely intact and are potentially immortal in the form of copies. So, genes should be
the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an
inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a
particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection
by describing life as a river of compatible genes flowing through geological time. Scoop up a
bucket of genes from the river of genes, and we have an organism serving as temporary bodies or
survival machines. A river of genes may fork into two branches representing two non-interbreeding
species as a result of geographical separation.
Gene targeting and implications
Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and
provides the mouse models for studying the roles of individual genes in embryonic development,
human disorders, aging and diseases. The mouse models, where one or more of its genes are
deactivated or made inoperable, are called knockout mice. Since the first reports in which
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homologous recombination in embryonic stem cells was used to generate gene-targeted mice, gene
targeting has proven to be a powerful means of precisely manipulating the mammalian genome,
producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations
that can be activated at specific time points, or in specific cells or organs, both during development
and in the adult animal.
Gene targeting strategies have been expanded to all kinds of modifications, including point
mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion
and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It
is predicted that the ability to generate mouse models with predictable phenotypes will have a
major impact on studies of all phases of development, immunology, neurobiology, oncology,
physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species
from which toti potent embryonic stem cells can be established, and therefore may offer a potential
to the improvement of domestic animals and plants.
Changing concept
The concept of the gene has changed considerably (see history section). From the original
definition of a "unit of inheritance", the term evolved to mean a DNA-based unit that can exert its
effects on the organism through RNA or protein products. It was also previously believed that one
gene makes one protein; this concept was overthrown by the discovery of alternative splicing and
trans-splicing.
The definition of a gene is still changing. The first cases of RNA-based inheritance have been
discovered in mammals. Evidence is also accumulating that the control regions of a gene do not
necessarily have to be close to the coding sequence on the linear molecule or even on the same
chromosome. Spilianakis and colleagues discovered that the promoter region of the interferongamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on
chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.
The concept that genes are clearly delimited is also being eroded. There is evidence for fused
proteins stemming from two adjacent genes that can produce two separate protein products. While
it is not clear whether these fusion proteins are functional, the phenomenon is more frequent than
previously thought. Even more ground-breaking than the discovery of fused genes is the
observation that some proteins can be composed of exons from far away regions and even different
chromosomes. This new data has led to an updated, and probably tentative, definition of a gene as
"a union of genomic sequences encoding a coherent set of potentially overlapping functional
products." This new definition categorizes genes by functional products, whether they be proteins
or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as
gene-associated regions.
Evolutionary Basis of Behaviour
Evolution of behaviour is based on the premise that some behaviors (both social and individual) are
at least partly inherited and can be affected by natural selection. It begins with the idea that
behaviors have evolved over time, similar to the way that physical traits are thought to have
evolved. It predicts therefore that animals will act in ways that have proven to be evolutionarily
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successful over time, which can among other things result in the formation of complex social
processes conducive to evolutionary fitness.
The discipline seeks to explain behavior as a product of natural selection. Behavior is therefore
seen as an effort to preserve one's genes in the population. Inherent in sociobiological reasoning is
the idea that certain genes or gene combinations that influence particular behavioral traits can be
inherited from generation to generation.
Introductory examples
For example, newly dominant male lions often will kill cubs in the pride that were not sired by
them. This behaviour is adaptive in evolutionary terms because killing the cubs eliminates
competition for their own offspring and causes the nursing females to come into heat faster, thus
allowing more of his genes to enter into the population. Sociobiologists would view this instinctual
cub-killing behavior as being inherited through the genes of successfully reproducing male lions,
whereas non-killing behaviour may have "died out" as those lions were less successful in
reproducing.
Genetic mouse mutants have now been harnessed to illustrate the power that genes exert on
behaviour. For example, the transcription factor FEV (aka Pet1) has been shown, through its role in
maintaining the serotonergic system in the brain, to be required for normal aggressive and anxietylike behavior. Thus, when FEV is genetically deleted from the mouse genome, male mice will
instantly attack other males, whereas their wild-type counterparts take significantly longer to
initiate violent behaviour. In addition, FEV has been shown to be required for correct maternal
behaviour in mice, such that their offspring do not survive unless cross-fostered to other wild-type
female mice
A genetic basis for instinctive behavioural traits among non-human species, such as in the above
example, is commonly accepted among many biologists; however, attempting to use a genetic basis
to explain complex behaviours in human societies has remained extremely controversial.
History
According to the OED, John Paul Scott coined the word "sociobiology" at a 1946 conference on
genetics and social behaviour, and became widely used after it was popularized by Edward O.
Wilson in his 1975 book, Sociobiology: The New Synthesis. However, the influence of evolution on
behavior has been of interest to biologists and philosophers since soon after the discovery of the
evolution itself. Peter Kropotkin's Mutual Aid: A Factor of Evolution, written in the early 1890s, is
a popular example. Antecedents of modern sociobiological thinking can be traced to the 1960s and
the work of such biologists as Robert Trivers and William D. Hamilton.
Nonetheless, it was Wilson's book that pioneered and popularized the attempt to explain the
evolutionary mechanics behind social behaviors such as altruism, aggression, and nurturence,
primarily in ants (Wilson's own research specialty) but also in other animals. The final chapter of
the book is devoted to sociobiological explanations of human behavior, and Wilson later wrote a
Pulitzer Prize winning book, On Human Nature, that addressed human behavior specifically.
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Sociobiological theory
Sociobiologists believe that human behavior, as well as nonhuman animal behavior, can be partly
explained as the outcome of natural selection. They contend that in order fully to understand
behavior, it must be analyzed in terms of evolutionary considerations.
Natural selection is fundamental to evolutionary theory. Variants of hereditary traits which increase
an organism's ability to survive and reproduce will be more greatly represented in subsequent
generations, i.e., they will be "selected for". Thus, inherited behavioral mechanisms that allowed an
organism a greater chance of surviving and/or reproducing in the past are more likely to survive in
present organisms. That inherited adaptive behaviors are present in nonhuman animal species has
been multiply demonstrated by biologists, and it has become a foundation of evolutionary biology.
However, there is continued resistance by some researchers over the application of evolutionary
models to humans, particularly from within the social sciences, where culture has long been
assumed to be the predominant driver of behavior.
Sociobiology is based upon two fundamental premises:

Certain behavioral traits are inherited,

Inherited behavioral traits have been honed by natural selection. Therefore, these traits were
probably "adaptive" in the species` evolutionarily evolved environment.
Sociobiology uses Nikolaas Tinbergen's four categories of questions and explanations of animal
behavior. Two categories are at the species level; two, at the individual level. The species-level
categories (often called “ultimate explanations”) are

the function (i.e., adaptation) that a behavior serves and

the evolutionary process (i.e., phylogeny) that resulted in this functionality.
The individual-level categories (often called “proximate explanations”) are

the development of the individual (i.e., ontogeny) and

the proximate mechanism (e.g., brain anatomy and hormones).
Sociobiologists are interested in how behavior can be explained logically as a result of
selective pressures in the history of a species. Thus, they are often interested in instinctive, or
intuitive behavior, and in explaining the similarities, rather than the differences, between cultures.
For example, mothers within many species of mammals – including humans – are very protective
of their offspring. Sociobiologists reason that this protective behavior likely evolved over time
because it helped those individuals which had the characteristic to survive and reproduce. Over
time, individuals who exhibited such protective behaviours would have had more surviving
offspring than did those who did not display such behaviours, such that this parental protection
would increase in frequency in the population. In this way, the social behavior is believed to have
evolved in a fashion similar to other types of nonbehavioral adaptations, such as (for example) fur
or the sense of smell.
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Individual genetic advantage often fails to explain certain social behaviors as a result of genecentred selection, and evolution may also act upon groups. The mechanisms responsible for group
selection employ paradigms and population statistics borrowed from game theory. E.O. Wilson
argued that altruistic individuals must reproduce their own altruistic genetic traits for altruism to
survive. When altruists lavish their resources on non-altruists at the expense of their own kind, the
altruists tend to die out and the others tend to grow. In other words, altruism is more likely to
survive if altruists practice the ethic that "charity begins at home."
Within sociobiology, a social behavior is first explained as a sociobiological hypothesis by finding
an evolutionarily stable strategy that matches the observed behavior. Stability of a strategy can be
difficult to prove, but usually, a well-formed strategy will predict gene frequencies. The hypothesis
can be supported by establishing a correlation between the gene frequencies predicted by the
strategy, and those expressed in a population. Measurement of genes and gene-frequencies can be
problematic, however, because a simple statistical correlation can be open to charges of circularity
(Circularity can occur if the measurement of gene frequency indirectly uses the same measurements
that describe the strategy).
Altruism between social insects and littermates has been explained in such a way. Altruistic
behavior in some animals has been correlated to the degree of genome shared between altruistic
individuals. A quantitative description of infanticide by male harem-mating animals when the alpha
male is displaced as well as rodent female infanticide and fetal resorption are active areas of study.
In general, females with more bearing opportunities may value offspring less, and may also arrange
bearing opportunities to maximize the food and protection from mates.
An important concept in sociobiology is that temperamental traits within a gene pool and between
gene pools exist in an ecological balance. Just as an expansion of a sheep population might
encourage the expansion of a wolf population, an expansion of altruistic traits within a gene pool
may also encourage the expansion of individuals with dependent traits.
Sociobiology is sometimes associated with arguments over the "genetic" basis of intelligence.
While sociobiology is predicated on the observation that genes do affect behavior, it is perfectly
consistent to be a sociobiologist while arguing that measured IQ variations between individuals
reflect mainly cultural or economic rather than genetic factors. However, many critics point out that
the usefulness of sociobiology as an explanatory tool breaks down once a trait is so variable as to
no longer be exposed to selective pressures. In order to explain aspects of human intelligence as the
outcome of selective pressures, it must be demonstrated that those aspects are inherited, or genetic,
but this does not necessarily imply differences among individuals: a common genetic inheritance
could be shared by all humans, just as the genes responsible for number of limbs are shared by all
individuals. An even more sensitive subject is race and intelligence.
Researchers performing twin studies have argued that differences between people on behavioral
traits such as creativity, extroversion and aggressiveness are between 45% to 75% due to genetic
differences, and intelligence is said by some to be about 80% genetic after one matures (discussed
at Intelligence quotient#Environment). However, critics (such as the evolutionary geneticist R. C
Lewontin) have highlighted serious flaws in twin studies, such as the inability of researchers to
separate environmental, genetic, and dialectic effects on twins.
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Criminality is actively under study, but extremely controversial. There are arguments that in some
environments criminal behavior might be adaptive.
Criticism
Many critics draw an intellectual link between sociobiology and biological determinism, the belief
that most human differences can be traced to specific genes rather than differences in culture or
social environments. Critics also draw parallels between biological determinism as an underlying
philosophy to the social Darwinian and eugenics movements of the early 20th century, and
controversies in the history of intelligence testing. Steven Pinker argues that critics have been
overly swayed by politics and a "fear" of biological determinism. However, all these critics have
claimed that sociobiology fails on scientific grounds, independent of their political critiques. In
particular, Lewontin, Rose & Kamin drew a detailed distinction between the politics and history of
an idea and its scientific validity, as has Stephen Jay Gould.
Wilson and his supporters counter the intellectual link by denying that Wilson had a political
agenda, still less a right-wing one. They pointed out that Wilson had personally adopted a number
of liberal political stances and had attracted progressive sympathy for his outspoken
environmentalism. They argued that as scientists they had a duty to uncover the truth whether that
was politically correct or not. They argued that sociobiology does not necessarily lead to any
particular political ideology as many critics implied. Many subsequent sociobiologists, including
Robert Wright, Anne Campbell, Frans de Waal and Sarah Blaffer Hrdy, have used sociobiology to
argue quite separate points. Noam Chomsky came to the defense of sociobiology's methodology,
noting that it was the same methodology he used in his work on linguistics. However, he roundly
criticized the sociobiologists' actual conclusions about humans as lacking substance. He also noted
that the anarchist Peter Kropotkin had made similar arguments in his book Mutual Aid: A Factor of
Evolution, although focusing more on altruism than aggression, suggesting that anarchist societies
were feasible because of an innate human tendency to cooperate.
Wilson's claims that he had never meant to imply what ought to be, only what is the case are
supported by his writings, which are descriptive, not prescriptive. However, many critics have
pointed out that the language of sociobiology often slips from "is" to "ought",leading
sociobiologists to make arguments against social reform on the basis that socially progressive
societies are at odds with our innermost nature. For example, some groups have supported positions
of ethnic nepotism. Views such as this, however, are often criticized as examples of the naturalistic
fallacy, when reasoning jumps from descriptions about what is to prescriptions about what ought to
be. (A common example is the justification of militarism if scientific evidence showed warfare was
part of human nature.) It has also been argued that opposition to stances considered anti-social,
such as ethnic nepotism, are based on moral assumptions, not bioscientific assumptions, meaning
that it is not vulnerable to being disproved by bioscientific advances. The history of this debate, and
others related to it, are covered in detail by Cronin (1992), Segerstråle (2000) and Alcock (2001).
Adaptationists such as Steven Pinker have also suggested that the debate has a strong ad hominem
component.
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Module 3
THE NEURON
Structure Function and Types of Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and
chemical signaling. Chemical signaling occurs via synapses, specialized connections with other
cells. Neurons connect to each other to form networks. Neurons are the core components of the
nervous system, which includes the brain, spinal cord, and peripheral ganglia. A number of
specialized types of neurons exist: sensory neurons respond to touch, sound, light and numerous
other stimuli affecting cells of the sensory organs that then send signals to the spinal cord and brain.
Motor neurons receive signals from the brain and spinal cord and cause muscle contractions and
affect glands. Interneurons connect neurons to other neurons within the same region of the brain or
spinal cord.
A typical neuron possesses a cell body (often called the soma), dendrites, and an axon. Dendrites
are filaments that arise from the cell body, often extending for hundreds of microns and branching
multiple times, giving rise to a complex "dendritic tree". An axon is a special cellular filament that
arises from the cell body at a site called the axon hillock and travels for a distance, as far as 1 m in
humans or even more in other species. The cell body of a neuron frequently gives rise to multiple
dendrites, but never to more than one axon, although the axon may branch hundreds of times before
it terminates. At the majority of synapses, signals are sent from the axon of one neuron to a dendrite
of another. There are, however, many exceptions to these rules: neurons that lack dendrites,
neurons that have no axon, synapses that connect an axon to another axon or a dendrite to another
dendrite, etc.
All neurons are electrically excitable, maintaining voltage gradients across their membranes by
means of metabolically driven ion pumps, which combine with ion channels embedded in the
membrane to generate intracellular-versus-extracellular concentration differences of ions such as
sodium, potassium, chloride, and calcium. Changes in the cross-membrane voltage can alter the
function of voltage-dependent ion channels. If the voltage changes by a large enough amount, an
all-or-none electrochemical pulse called an action potential is generated, which travels rapidly
along the cell's axon, and activates synaptic connections with other cells when it arrives.
Neurons of the adult brain do not generally undergo cell division, and usually cannot be replaced
after being lost, although there are a few known exceptions. In most cases they are generated by
special types of stem cells, although astrocytes (a type of glial cell) have been observed to turn into
neurons as they are sometimes pluripotent.
Overview
A neuron is a special type of cell that is found in the bodies of most animals (all members of the
group Eumetazoa, to be precise—this excludes only sponges and a few other very simple animals).
The features that define a neuron are electrical excitability and the presence of synapses, which are
complex membrane junctions used to transmit signals to other cells. The body's neurons, plus the
glial cells that give them structural and metabolic support, together constitute the nervous system.
In vertebrates, the majority of neurons belong to the central nervous system, but some reside in
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peripheral ganglia, and many sensory neurons are situated in sensory organs such as the retina and
cochlea.
Although neurons are very diverse and there are exceptions to nearly every rule, it is convenient to
begin with a schematic description of the structure and function of a "typical" neuron. A typical
neuron is divided into three parts: the soma or cell body, dendrites, and axon. The soma is usually
compact; the axon and dendrites are filaments that extrude from it. Dendrites typically branch
profusely, getting thinner with each branching, and extending their farthest branches a few hundred
microns from the soma. The axon leaves the soma at a swelling called the axon hillock, and can
extend for great distances, giving rise to hundreds of branches. Unlike dendrites, an axon usually
maintains the same diameter as it extends. The soma may give rise to numerous dendrites, but
never to more than one axon. Synaptic signals from other neurons are received by the soma and
dendrites; signals to other neurons are transmitted by the axon. A typical synapse, then, is a contact
between the axon of one neuron and a dendrite or soma of another. Synaptic signals may be
excitatory or inhibitory. If the net excitation received by a neuron over a short period of time is
large enough, the neuron generates a brief pulse called an action potential, which originates at the
soma and propagates rapidly along the axon, activating synapses onto other neurons as it goes.
Many neurons fit the foregoing schema in every respect, but there are also exceptions to most parts
of it. There are no neurons that lack a soma, but there are neurons that lack dendrites, and others
that lack an axon. Furthermore, in addition to the typical axodendritic and axosomatic synapses,
there are axoaxonic (axon-to-axon) and dendrodendritic (dendrite-to-dendrite) synapses.
The key to neural function is the synaptic signalling process, which is partly electrical and partly
chemical. The electrical aspect depends on properties of the neuron's membrane. Like all animal
cells, every neuron is surrounded by a plasma membrane, a bilayer of lipid molecules with many
types of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator, but in
neurons, many of the protein structures embedded in the membrane are electrically active. These
include ion channels that permit electrically charged ions to flow across the membrane, and ion
pumps that actively transport ions from one side of the membrane to the other. Most ion channels
are permeable only to specific types of ions. Some ion channels are voltage gated, meaning that
they can be switched between open and closed states by altering the voltage difference across the
membrane. Others are chemically gated, meaning that they can be switched between open and
closed states by interactions with chemicals that diffuse through the extracellular fluid. The
interactions between ion channels and ion pumps produce a voltage difference across the
membrane, typically a bit less than 1/10 of a volt at baseline. This voltage has two functions: first, it
provides a power source for an assortment of voltage-dependent protein machinery that is
embedded in the membrane; second, it provides a basis for electrical signal transmission between
different parts of the membrane.
Neurons communicate by chemical and electrical synapses in a process known as synaptic
transmission. The fundamental process that triggers synaptic transmission is the action potential, a
propagating electrical signal that is generated by exploiting the electrically excitable membrane of
the neuron. This is also known as a wave of depolarization.
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Anatomy and histology
Neurons are highly specialized for the processing and transmission of cellular signals. Given the
diversity of functions performed by neurons in different parts of the nervous system, there is, as
expected, a wide variety in the shape, size, and electrochemical properties of neurons. For instance,
the soma of a neuron can vary from 4 to 100 micrometers in diameter.
* The soma is the central part of the neuron. It contains the nucleus of the cell, and therefore is
where most protein synthesis occurs. The nucleus ranges from 3 to 18 micrometers in diameter.
* The dendrites of a neuron are cellular extensions with many branches, and metaphorically this
overall shape and structure is referred to as a dendritic tree. This is where the majority of input to
the neuron occurs.
* The axon is a finer, cable-like projection which can extend tens, hundreds, or even tens of
thousands of times the diameter of the soma in length. The axon carries nerve signals away from
the soma (and also carries some types of information back to it). Many neurons have only one axon,
but this axon may—and usually will—undergo extensive branching, enabling communication with
many target cells. The part of the axon where it emerges from the soma is called the axon hillock.
Besides being an anatomical structure, the axon hillock is also the part of the neuron that has the
greatest density of voltage-dependent sodium channels. This makes it the most easily-excited part
of the neuron and the spike initiation zone for the axon: in electrophysiological terms it has the
most negative action potential threshold. While the axon and axon hillock are generally involved in
information outflow, this region can also receive input from other neurons.
* The axon terminal contains synapses, specialized structures where neurotransmitter chemicals
are released in order to communicate with target neurons.
Although the canonical view of the neuron attributes dedicated functions to its various anatomical
components, dendrites and axons often act in ways contrary to their so-called main function.
Axons and dendrites in the central nervous system are typically only about one micrometer thick,
while some in the peripheral nervous system are much thicker. The soma is usually about 10–25
micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest
axon of a human motoneuron can be over a meter long, reaching from the base of the spine to the
toes. Sensory neurons have axons that run from the toes to the dorsal columns, over 1.5 meters in
adults. Giraffes have single axons several meters in length running along the entire length of their
necks. Much of what is known about axonal function comes from studying the squid giant axon, an
ideal experimental preparation because of its relatively immense size (0.5–1 millimeters thick,
several centimeters long).
Fully differentiated neurons are permanently amitotic; however, recent research shows that
additional neurons throughout the brain can originate from neural stem cells found throughout the
brain but in particularly high concentrations in the subventricular zone and subgranular zone
through the process of neurogenesis.
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Histology and internal structure
Nerve cell bodies stained with basophilic dyes show numerous microscopic clumps of Nissl
substance (named after German psychiatrist and neuropathologist Franz Nissl, 1860–1919), which
consists of rough endoplasmic reticulum and associated ribosomal RNA. The prominence of the
Nissl substance can be explained by the fact that nerve cells are metabolically very active, and
hence are involved in large amounts of protein synthesis.
The cell body of a neuron is supported by a complex meshwork of structural proteins called
neurofilaments, which are assembled into larger neurofibrils. Some neurons also contain pigment
granules, such as neuromelanin (a brownish-black pigment, byproduct of synthesis of
catecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).
There are different internal structural characteristics between axons and dendrites. Typical axons
almost never contain ribosomes, except some in the initial segment. Dendrites contain granular
endoplasmic reticulum or ribosomes, with diminishing amounts with distance from the cell body.
Classes
Neurons exist in a number of different shapes and sizes and can be classified by their morphology
and function. The anatomist Camillo Golgi grouped neurons into two types; type I with long axons
used to move signals over long distances and type II with short axons, which can often be confused
with dendrites. Type I cells can be further divided by where the cell body or soma is located. The
basic morphology of type I neurons, represented by spinal motor neurons, consists of a cell body
called the soma and a long thin axon which is covered by the myelin sheath. Around the cell body
is a branching dendritic tree that receives signals from other neurons. The end of the axon has
branching terminals (axon terminal) that release neurotransmitters into a gap called the synaptic
cleft between the terminals and the dendrites of the next neuron.
Structural classification
Polarity
Most neurons can be anatomically characterized as:
* Unipolar or pseudounipolar: dendrite and axon emerging from same process.
* Bipolar: axon and single dendrite on opposite ends of the soma.
* Multipolar: more than two dendrites:
o Golgi I: neurons with long-projecting axonal processes; examples are pyramidal cells, Purkinje
cells, and anterior horn cells.
o Golgi II: neurons whose axonal process projects locally; the best example is the granule cell.
Other
Furthermore, some unique neuronal types can be identified according to their location in the
nervous system and distinct shape. Some examples are:
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* Basket cells, interneurons that form a dense plexus of terminals around the soma of target cells,
found in the cortex and cerebellum.
* Betz cells, large motor neurons.
* Medium spiny neurons, most neurons in the corpus striatum.
* Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar neuron.
* Pyramidal cells, neurons with triangular soma, a type of Golgi I.
* Renshaw cells, neurons with both ends linked to alpha motor neurons.
* Granule cells, a type of Golgi II neuron.
* anterior horn cells, motoneurons located in the spinal cord.
Functional classification
Direction
* Afferent neurons convey information from tissues and organs into the central nervous system
and are sometimes also called sensory neurons.
* Efferent neurons transmit signals from the central nervous system to the effector cells and are
sometimes called motor neurons.
* Interneurons connect neurons within specific regions of the central nervous system.
Afferent and efferent can also refer generally to neurons which, respectively, bring information to
or send information from the brain region.
Action on other neurons
A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors.
The effect upon the target neuron is determined not by the source neuron or by the
neurotransmitter, but by the type of receptor that is activated. A neurotransmitter can be thought of
as a key, and a receptor as a lock: the same type of key can here be used to open many different
types of locks. Receptors can be classified broadly as excitatory (causing an increase in firing rate),
inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting effects not
directly related to firing rate).
In fact, however, the two most common neurotransmitters in the brain, glutamate and GABA, have
actions that are largely consistent. Glutamate acts on several different types of receptors, but most
of them have effects that are excitatory. Similarly GABA acts on several different types of
receptors, but all of them have effects (in adult animals, at least) that are inhibitory. Because of this
consistency, it is common for neuroscientists to simplify the terminology by referring to cells that
release glutamate as "excitatory neurons," and cells that release GABA as "inhibitory neurons."
Since well over 90% of the neurons in the brain release either glutamate or GABA, these labels
encompass the great majority of neurons. There are also other types of neurons that have consistent
effects on their targets, for example "excitatory" motor neurons in the spinal cord that release
acetylcholine, and "inhibitory" spinal neurons that release glycine.
The distinction between excitatory and inhibitory neurotransmitters is not absolute, however.
Rather, it depends on the class of chemical receptors present on the target neuron. In principle, a
single neuron, releasing a single neurotransmitter, can have excitatory effects on some targets,
inhibitory effects on others, and modulatory effects on others still. For example, photoreceptors in
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the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFF
bipolar cells are, like most neurons, excited by the released glutamate. However, neighboring target
neurons called ON bipolar cells are instead inhibited by glutamate, because they lack the typical
ionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamate
receptors. When light is present, the photoreceptors cease releasing glutamate, which relieves the
ON bipolar cells from inhibition, activating them; this simultaneously removes the excitation from
the OFF bipolar cells, silencing them.
Discharge patterns
Neurons can be classified according to their electrophysiological characteristics:
* Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example:
interneurons in neurostriatum.
* Phasic or bursting. Neurons that fire in bursts are called phasic.
* Fast spiking. Some neurons are notable for their fast firing rates, for example some types of
cortical inhibitory interneurons, cells in globus pallidus, retinal ganglion cells.
Classification by neurotransmitter production
Neurons differ in the type of neurotransmitter they manufacture. Some examples are
* Cholinergic Neurons - acetylcholine
Acetylcholine is released from presynaptic neurons into the synaptic cleft. It acts as a ligand for
both ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinic
receptors, are pentameric ligand-gated ion channels composed of alpha and beta subunits that bind
nicotine. Ligand binding opens the channel causing influx of Na+ depolarization and increases the
probability of presynaptic neurotransmitter release.
* GABAergic neurons - gamma aminobutyric acid
GABA is one of two neuroinhibitors in the CNS, the other being Glycine. GABA has a
homologous function to ACh, gating anion channels that allow Cl- ions to enter the post synaptic
neuron. Cl- causes hyperpolarization within the neuron, decreasing the probability of an action
potential firing as the voltage becomes more negative (recall that for an action potential to fire, a
positive voltage threshold must be reached).
* Glutamatergic Neurons - glutamate
Glutamate is one of two primary excitatory amino acids, the other being Aspartate. Glutamate
receptors are one of four categories, three of which are ligand-gated ion channels and one of which
is a G-protein coupled receptor (often referred to as GPCR). 1 - AMPA and Kainate receptors both
function as cation channels permeable to Na+ cation channels mediating fast excitatory synaptic
transmission 2 - NMDA receptors are another cation channel that is more permeable to Ca2+. The
function of NMDA receptors is dependant on Glycine receptor binding as a co-agonist within the
channel pore. NMDA receptors will not function without both ligands present. 3 - Metabotropic
receptors, GPCRs modulate synaptic transmission and postsynaptic excitability. Glutamate can
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cause excitotoxicity when blood flow to the brain is interrupted, resulting in brain damage. When
blood flow is suppressed, glutamate is released from presynaptic neurons causing NMDA and
AMPA receptor activation moreso than would normally be the case outside of stress conditions,
leading to elevated Ca2+ and Na+ entering the post synaptic neuron and cell damage.
* dopaminergic neurons - dopamine
Dopamine is a neurotransmitter that acts on D1 type (D1 and D5) Gs coupled receptors which
increase cAMP and PKA or D2 type (D2,D3 and D4)receptors which activate Gi-coupled receptors
that decrease cAMP and PKA. Dopamine is connected to mood and behavior, and modulates both
pre and post synaptic neurotransmission. Loss of dopamine neurons in the substantia nigra has been
linked to Parkinson's disease.
* Serotonergic Neurons - serotonin
Serotonin,(5-Hydroxytryptamine, 5-HT), can act as excitatory or inhibitory. Of the four 5-HT
receptor classes, 3 are GPCR and 1 is ligand gated cation channel. Serotonin is synthesized from
tryptophan by tryptophan hydroxylase, and then further by aromatic acid decarboxylase. A lack of
5-HT at postsynaptic neurons has been linked to depression. Drugs that block the presynaptic
serotonin transporter are used for treatment, such as Prozac and Zoloft.
Connectivity
Neurons communicate with one another via synapses, where the axon terminal or en passant
boutons (terminals located along the length of the axon) of one cell impinges upon another neuron's
dendrite, soma or, less commonly, axon. Neurons such as Purkinje cells in the cerebellum can have
over 1000 dendritic branches, making connections with tens of thousands of other cells; other
neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two
dendrites, each of which receives thousands of synapses. Synapses can be excitatory or inhibitory
and will either increase or decrease activity in the target neuron. Some neurons also communicate
via electrical synapses, which are direct, electrically-conductive junctions between cells.
In a chemical synapse, the process of synaptic transmission is as follows: when an action potential
reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter
the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with
the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across
the synaptic cleft and activate receptors on the postsynaptic neuron.
The human brain has a huge number of synapses. Each of the 1011 (one hundred billion) neurons
has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a
three-year-old child has about 1015 synapses (1 quadrillion). This number declines with age,
stabilizing by adulthood. Estimates vary for an adult, ranging from 1014 to 5 x 1014 synapses (100
to 500 trillion).
Mechanisms for propagating action potentials
In 1937, John Zachary Young suggested that the squid giant axon could be used to study neuronal
electrical properties. Being larger than but similar in nature to human neurons, squid cells were
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easier to study. By inserting electrodes into the giant squid axons, accurate measurements were
made of the membrane potential.
The cell membrane of the axon and soma contain voltage-gated ion channels which allow the
neuron to generate and propagate an electrical signal (an action potential). These signals are
generated and propagated by charge-carrying ions including sodium (Na+), potassium (K+),
chloride (Cl-), and calcium (Ca2+).
There are several stimuli that can activate a neuron leading to electrical activity, including pressure,
stretch, chemical transmitters, and changes of the electric potential across the cell membrane.
Stimuli cause specific ion-channels within the cell membrane to open, leading to a flow of ions
through the cell membrane, changing the membrane potential.
Thin neurons and axons require less metabolic expense to produce and carry action potentials, but
thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining
rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths
are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the
peripheral nervous system. The sheath enables action potentials to travel faster than in
unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral
nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes
of Ranvier which contain a high density of voltage-gated ion channels. Multiple sclerosis is a
neurological disorder that results from demyelination of axons in the central nervous system.
Some neurons do not generate action potentials, but instead generate a graded electrical signal,
which in turn causes graded neurotransmitter release. Such nonspiking neurons tend to be sensory
neurons or interneurons, because they cannot carry signals long distances.
Neural coding
Neural coding is concerned with how sensory and other information is represented in the brain by
neurons. The main goal of studying neural coding is to characterize the relationship between the
stimulus and the individual or ensemble neuronal responses, and the relationships amongst the
electrical activities of the neurons within the ensemble. It is thought that neurons can encode both
digital and analog information.
All-or-none principle
The conduction of nerve impulses is an example of an all-or-none response. In other words, if a
neuron responds at all, then it must respond completely. The greater the intensity of stimulation
does not produce a stronger signal but can produce more impulses per second. There are different
types of receptor response to stimulus, slowly adapting or tonic receptors respond to steady
stimulus and produce a steady rate of firing. These tonic receptors most often respond to increased
intensity of stimulus by increasing their firing frequency, usually as a power function of stimulus
plotted against impulses per second. This can be likened to an intrinsic property of light where to
get greater intensity of a specific frequency (color) there have to be more photons, as the photons
can't become "stronger" for a specific frequency.
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There are a number of other receptor types that are called quickly-adapting or phasic receptors,
where firing decreases or stops with steady stimulus; examples include: skin when touched by an
object causes the neurons to fire, but if the object maintains even pressure against the skin, the
neurons stop firing. The neurons of the skin and muscles that are responsive to pressure and
vibration have filtering accessory structures that aid their function. The pacinian corpuscle is one
such structure; it has concentric layers like an onion which form around the axon terminal. When
pressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon,
which fires. If the pressure is steady, there is no more stimulus; thus, typically these neurons
respond with a transient depolarization during the initial deformation and again when the pressure
is removed, which causes the corpuscle to change shape again. Other types of adaptation are
important in extending the function of a number of other neurons.
History
The term neuron was coined by the German anatomist Heinrich Wilhelm Waldeyer. The neuron's
place as the primary functional unit of the nervous system was first recognized in the early 20th
century through the work of the Spanish anatomist Santiago Ramón y Cajal. Cajal proposed that
neurons were discrete cells that communicated with each other via specialized junctions, or spaces,
between cells. This became known as the neuron doctrine, one of the central tenets of modern
neuroscience. To observe the structure of individual neurons, Cajal used a silver staining method
developed by his rival, Camillo Golgi. The Golgi stain is an extremely useful method for
neuroanatomical investigations because, for reasons unknown, it stains a very small percentage of
cells in a tissue, so one is able to see the complete micro structure of individual neurons without
much overlap from other cells in the densely packed brain.
The neuron doctrine
The neuron doctrine is the now fundamental idea that neurons are the basic structural and
functional units of the nervous system. The theory was put forward by Santiago Ramón y Cajal in
the late 19th century. It held that neurons are discrete cells (not connected in a meshwork), acting as
metabolically distinct units.
Later discoveries yielded a few refinements to the simplest form of the doctrine. For example, glial
cells, which are not considered neurons, play an essential role in information processing. Also,
electrical synapses are more common than previously thought, meaning that there are direct,
cytoplasmic connections between neurons. In fact, there are examples of neurons forming even
tighter coupling: the squid giant axon arises from the fusion of multiple axons.
Cajal also postulated the Law of Dynamic Polarization, which states that a neuron receives signals
at its dendrites and cell body and transmits them, as action potentials, along the axon in one
direction: away from the cell body. The Law of Dynamic Polarization has important exceptions;
dendrites can serve as synaptic output sites of neurons and axons can receive synaptic inputs
Neurons in the brain
The number of neurons in the brain varies dramatically from species to species. One estimate puts
the human brain at about 100 billion (1011) neurons and 100 trillion (1014) synapses. Another
estimate is 86 billion neurons of which 16.3 billion are in the cerebral cortex and 69 billion in the
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cerebellum. By contrast, the nematode worm Caenorhabditis elegans has just 302 neurons making it
an ideal experimental subject as scientists have been able to map all of the organism's neurons. The
fruit fly Drosophila melanogaster, a common subject in biology experiments, has around 100,000
neurons and exhibits many complex behaviors. Many properties of neurons, from the type of
neurotransmitters used to ion channel composition, are maintained across species, allowing
scientists to study processes occurring in more complex organisms in much simpler experimental
systems.
Neurological disorders
Charcot-Marie-Tooth disease (CMT), also known as Hereditary Motor and Sensory Neuropathy
(HMSN), Hereditary Sensorimotor Neuropathy (HMSN), or Peroneal Muscular Atrophy, is a
heterogeneous inherited disorder of nerves (neuropathy) that is characterized by loss of muscle
tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the
advanced stages of disease. Presently incurable, this disease is one of the most common inherited
neurological disorders, with 37 in 100,000 affected.
Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease
characterized by progressive cognitive deterioration together with declining activities of daily
living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is
loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes
steadily more pronounced with illness progression, with relative preservation of older memories.
As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language
(aphasia), skilled movements (apraxia), recognition (agnosia), and functions such as decisionmaking and planning get impaired.
Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the
central nervous system that often impairs the sufferer's motor skills and speech. Parkinson's disease
belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity,
tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical
movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor
cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine,
which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include
high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
Myasthenia Gravis is a neuromuscular disease leading to fluctuating muscle weakness and
fatigability. Weakness is typically caused by circulating antibodies that block acetylcholine
receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the
neurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants, cholinesterase
inhibitors and, in selected cases, thymectomy.
Demyelination
Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves.
When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerve
eventually withers. This leads to certain neurodegenerative disorders like multiple sclerosis, chronic
inflammatory demyelinating polyneuropathy.
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Axonal degeneration
Although most injury responses include a calcium influx signaling to promote resealing of severed
parts, axonal injuries initially lead to acute axonal degeneration (AAD), which is rapid separation
of the proximal and distal ends within 30 minutes of injury. Degeneration follows with swelling of
the axolemma, and eventually leads to bead like formation. Granular disintegration of the axonal
cytoskeleton and inner organelles occurs after axolemma degradation. Early changes include
accumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulum
degrades and mitochondria swell up and eventually disintegrate. The disintegration is dependent on
Ubiquitin and Calpain proteases (caused by influx of calcium ion), suggesting that axonal
degeneration is an active process. Thus the axon undergoes complete fragmentation. The process
takes about roughly 24 hrs in the PNS, and longer in the CNS. The signaling pathways leading to
axolemma degeneration are currently unknown.
Nerve regeneration
It has been demonstrated that neurogenesis can sometimes occur in the adult vertebrate brain, and it
is often possible for peripheral axons to regrow if they are severed. The latter can take a long time:
after a nerve injury to the human arm, for example, it may take months for feeling to return to the
hands and fingers.
Action potential (Nerve Impulses)
Action Potentials in neurons are also known as nerve impulses or spikes. In physiology, an action
potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises
and falls, following a stereotyped trajectory. Action potentials occur in several types of animal
cells, called excitable cells, which include neurons, muscle cells, and endocrine cells. In neurons,
they play a central role in cell-to-cell communication. In other types of cells, their main function is
to activate intracellular processes. In muscle cells, for example, an action potential is the first step
in the chain of events leading to contraction. In beta cells of the pancreas, they provoke release of
insulin. Action potentials in neurons are also known as "nerve impulses" or "spikes", and the
temporal sequence of action potentials generated by a neuron is called its "spike train". A neuron
that emits an action potential is often said to "fire".
Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's
plasma membrane. These channels are shut when the membrane potential is near the resting
potential of the cell, but they rapidly begin to open if the membrane potential increases to a
precisely defined threshold value. When the channels open, they allow an inward flow of sodium
ions, which changes the electrochemical gradient, which in turn produces a further rise in the
membrane potential. This then causes more channels to open, producing a greater electrical current,
and so on. The process proceeds explosively until all of the available ion channels are open,
resulting in a large upswing in the membrane potential. The rapid influx of sodium ions causes the
polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As the
sodium channels close, sodium ions can no longer enter the neuron, and they are actively
transported out the plasma membrane. Potassium channels are then activated, and there is an
outward current of potassium ions, returning the electrochemical gradient to the resting state. After
an action potential has occurred, there is a transient negative shift, called the afterhyperpolarization
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or refractory period, due to additional potassium currents. This is the mechanism which prevents an
action potential traveling back the way it just came.
In animal cells, there are two primary types of action potentials, one type generated by voltagegated sodium channels, the other by voltage-gated calcium channels. Sodium-based action
potentials usually last for less than one millisecond, whereas calcium-based action potentials may
last for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide the
driving force for a long burst of rapidly-emitted sodium spikes. In cardiac muscle cells, on the other
hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike,
which then produces muscle contraction.
Overview for a typical neuron
All cells in animal body tissues are electrically polarized—in other words, they maintain a voltage
difference across the cell's plasma membrane, known as the membrane potential. This electrical
polarization results from a complex interplay between protein structures embedded in the
membrane called ion pumps and ion channels. In neurons, the types of ion channels in the
membrane usually vary across different parts of the cell, giving the dendrites, axon, and cell body
different electrical properties. As a result, some parts of the membrane of a neuron may be
excitable (capable of generating action potentials) while others are not. The most excitable part of a
neuron is usually the axon hillock (the point where the axon leaves the cell body), but the axon and
cell body are also excitable in most cases.
Each excitable patch of membrane has two important levels of membrane potential: the resting
potential, which is the value the membrane potential maintains as long as nothing perturbs the cell,
and a higher value called the threshold potential. At the axon hillock of a typical neuron, the resting
potential is around -70 millivolts (mV) and the threshold potential is around -55 mV. Synaptic
inputs to a neuron cause the membrane to depolarize or hyperpolarize; that is, they cause the
membrane potential to rise or fall. Action potentials are triggered when enough depolarization
accumulates to bring the membrane potential up to threshold. When an action potential is triggered,
the membrane potential abruptly shoots upward, often reaching as high as +100 mV, then equally
abruptly shoots back downward, often ending below the resting level, where it remains for some
period of time. The shape of the action potential is stereotyped; that is, the rise and fall usually have
approximately the same amplitude and time course for all action potentials in a given cell.
(Exceptions are discussed later in the article.) In most neurons, the entire process takes place in less
than a thousandth of a second. Many types of neurons emit action potentials constantly at rates of
up to 10-100 per second; some types, however, are much quieter, and may go for minutes or longer
without emitting any action potentials.
At the biophysical level, action potentials result from special types of voltage-gated ion channels.
As the membrane potential is increased, sodium ion channels open, allowing the entry of sodium
ions into the cell. This is followed by the opening of potassium ion channels that permit the exit of
potassium ions from the cell. The inward flow of sodium ions increases the concentration of
positively-charged cations in the cell and causes depolarization, where the potential of the cell is
higher than the cell's resting potential. The sodium channels close at the peak of the action
potential, while potassium continues to leave the cell. The efflux of potassium ions decreases the
membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium
current exceeds the sodium current and the voltage returns to its normal resting value, typically 70
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mV. However, if the voltage increases past a critical threshold, typically 15 mV higher than the
resting value, the sodium current dominates. This results in a runaway condition whereby the
positive feedback from the sodium current activates even more sodium channels. Thus, the cell
"fires," producing an action potential.
Currents produced by the opening of voltage-gated channels in the course of an action potential are
typically significantly larger than the initial stimulating current. Thus the amplitude, duration, and
shape of the action potential are largely determined by the properties of the excitable membrane
and not the amplitude or duration of the stimulus. This all-or-nothing property of the action
potential sets it apart from graded potentials such as receptor potentials, electrotonic potentials, and
synaptic potentials, which scale with the magnitude of the stimulus. A variety of action potential
types exist in many cell types and cell compartments as determined by the types of voltage-gated
channels, leak channels, channel distributions, ionic concentrations, membrane capacitance,
temperature, and other factors.
The principal ions involved in an action potential are sodium and potassium cations; sodium ions
enter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross the
membrane for the membrane voltage to change drastically. The ions exchanged during an action
potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The
few ions that do cross are pumped out again by the continual action of the sodium–potassium
pump, which, with other ion transporters, maintains the normal ratio of ion concentrations across
the membrane. Calcium cations and chloride anions are involved in a few types of action potentials,
such as the cardiac action potential and the action potential in the single-celled alga Acetabularia,
respectively.
Although action potentials are generated locally on patches of excitable membrane, the resulting
currents can trigger action potentials on neighboring stretches of membrane, precipitating a
domino-like propagation. In contrast to passive spread of electric potentials (electrotonic potential),
action potentials are generated anew along excitable stretches of membrane and propagate without
decay.Myelinated sections of axons are not excitable and do not produce action potentials and the
signal is propagated passively as electrotonic potential. Regularly spaced unmyelinated patches,
called the nodes of Ranvier, generate action potentials to boost the signal. Known as saltatory
conduction, this type of signal propagation provides a favorable tradeoff of signal velocity and axon
diameter. Depolarization of axon terminals, in general, triggers the release of neurotransmitter into
the synaptic cleft. In addition, backpropagating action potentials have been recorded in the
dendrites of pyramidal neurons, which are ubiquitous in the neocortex. These are thought to have a
role in spike-timing-dependent plasticity.
Biophysical and cellular context
Electrical signals within biological organisms are, in general, driven by ions. The most important
cations for the action potential are sodium (Na+) and potassium (K+). Both of these are monovalent
cations that carry a single positive charge. Action potentials can also involve calcium (Ca2+),
which is a divalent cation that carries a double positive charge. The chloride anion (Cl−) plays a
major role in the action potentials of some algae, but plays a negligible role in the action potentials
of most animals.
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Ions cross the cell membrane under two influences: diffusion and electric fields. A simple example
wherein two solutions - A and B - are separated by a porous barrier illustrates that diffusion will
ensure that they will eventually mix into equal solutions. This mixing occurs because of the
difference in their concentrations. The region with high concentration will diffuse out toward the
region with low concentration. To extend the example, let solution A have 30 sodium ions and 30
chloride ions. Also, let solution B have only 20 sodium ions and 20 chloride ions. Assuming the
barrier allows both types of ions to travel through it, then a steady state will be reached whereby
both solutions have 25 sodium ions and 25 chloride ions. If, however, the porous barrier is selective
to which ions are let through, then diffusion alone will not determine the resulting solution.
Returning to the previous example, let's now construct a barrier that is permeable only to sodium
ions. Since solution B has a lower concentration of both sodium and chloride, the barrier will attract
both ions from solution A. However, only sodium will travel through the barrier. This will result in
an accumulation of sodium in solution B. Since sodium has a positive charge, this accumulation
will make solution B more positive relative to solution A. Positive sodium ions will be less likely to
travel to the now-more-positive B solution. This constitutes the second factor controlling ion flow,
namely electric fields. The point at which this electric field completely counteracts the force due to
diffusion is called the equilibrium potential. At this point, the net flow of this specific ion (in this
case sodium) is zero.
Cell membrane
Each neuron is encased in a cell membrane, made of a phospholipid bilayer. This membrane is
nearly impermeable to ions. To transfer ions into and out of the neuron, the membrane provides two
structures. Ion pumps use the cell's energy to continuously move ions in and out. They create
concentration differences (between the inside and outside of the neuron) by transporting ions
against their concentration gradients (from regions of low concentration to regions of high
concentration). The ion channels then use this concentration difference to transport ions down their
concentration gradients (from regions of high concentration to regions of low concentration).
However, unlike the continuous transport by the ion pumps, the transport by the ion channels is
noncontinuous. They open and close in response to signals only from their environment. This
transport of ions through the ion channels then changes the voltage of the cell membrane. These
changes are what bring about an action potential. As an analogy, ion pumps play the role of the
battery that allows a radio circuit (the ion channels) to transmit a signal (action potential).
Membrane potential
The cell membrane acts as a barrier that prevents the inside solution (intracellular fluid) from
mixing with the outside solution (extracellular fluid). These two solutions have different
concentrations of their ions. Furthermore, this difference in concentrations leads to a difference in
charge of the solutions. This creates a situation whereby one solution is more positive than the
other. Therefore, positive ions will tend to gravitate towards the negative solution. Likewise,
negative ions will tend to gravitate towards the positive solution. To quantify this property, one
would like to somehow capture this relative positivity (or negativity). To do this, the outside
solution is set as the zero voltage. Then the difference between the inside voltage and the zero
voltage is determined. For example, if the outside voltage is 100 mV, and the inside voltage is 30
mV, then the difference is 70 mV. This difference is what is commonly referred to as the membrane
potential.
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Ion channels
Ion channels are integral membrane proteins with a pore through which ions can travel between
extracellular space and cell interior. Most channels are specific (selective) for one ion; for example,
most potassium channels are characterized by 1000:1 selectivity ratio for potassium over sodium,
though potassium and sodium ions have the same charge and differ only slightly in their radius. The
channel pore is typically so small that ions must pass through it in single-file order. Channel pore
can be either open or closed for ion passage, although a number of channels demonstrate various
sub-conductance levels. When a channel is open, ions permeate through the channel pore down the
transmembrane concentration gradient for that particular ion. Rate of ionic flow through the
channel, i.e. single-channel current amplitude, is determined by the maximum channel conductance
and electrochemical driving force for that ion, which is the difference between instantaneous value
of the membrane potential and the value of the reversal potential.
A channel may have several different states (corresponding to different conformations of the
protein), but each such state is either open or closed. In general, closed states correspond either to a
contraction of the pore — making it impassable to the ion — or to a separate part of the protein,
stoppering the pore. For example, the voltage-dependent sodium channel undergoes inactivation, in
which a portion of the protein swings into the pore, sealing it. This inactivation shuts off the
sodium current and plays a critical role in the action potential.
Ion channels can be classified by how they respond to their environment. For example, the ion
channels involved in the action potential are voltage-sensitive channels; they open and close in
response to the voltage across the membrane. Ligand-gated channels form another important class;
these ion channels open and close in response to the binding of a ligand molecule, such as a
neurotransmitter. Other ion channels open and close with mechanical forces. Still other ion
channels—such as those of sensory neurons—open and close in response to other stimuli, such as
light, temperature or pressure.
Ion pumps
The ionic currents of the action potential flow in response to concentration differences of the ions
across the cell membrane. These concentration differences are established by ion pumps, which are
integral membrane proteins that carry out active transport, i.e., use cellular energy (ATP) to "pump"
the ions against their concentration gradient. Such ion pumps take in ions from one side of the
membrane (decreasing its concentration there) and release them on the other side (increasing its
concentration there). The ion pump most relevant to the action potential is the sodium–potassium
pump, which transports three sodium ions out of the cell and two potassium ions in. As a
consequence, the concentration of potassium ions K+ inside the neuron is roughly 20-fold larger
than the outside concentration, whereas the sodium concentration outside is roughly ninefold larger
than inside. In a similar manner, other ions have different concentrations inside and outside the
neuron, such as calcium, chloride and magnesium.
Ion pumps influence the action potential only by establishing the relative ratio of intracellular and
extracellular ion concentrations. The action potential involves mainly the opening and closing of
ion channels, not ion pumps. If the ion pumps are turned off by removing their energy source, or by
adding an inhibitor such as ouabain, the axon can still fire hundreds of thousands of action
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potentials before their amplitudes begin to decay significantly. In particular, ion pumps play no
significant role in the repolarization of the membrane after an action potential.
Resting potential
As described in the section Ions and the forces driving their motion, equilibrium or reversal
potential of an ion is the value of transmembrane voltage at which the electric force generated by
diffusional movement of the ion down its concentration gradient becomes equal to the molecular
force of that diffusion. The equilibrium potential for any ion can be calculated using the Nernst
equation.
Generation of resting membrane potential is explicitly explained by the Goldman equation. The
resting plasma membrane of most animal cells is much more permeable to K+, which results in the
resting potential Vrest to be close to the potassium equilibrium potential.
It is important to realize that ionic and water permeability of a pure lipid bilayer is very small, and
it is, in a similar manner, negligible for ions of comparable size, such as Na+ and K+. The cell
membranes, however, contain a large number of ion channels, water channels (aquaporins), and
various ionic pumps, exchangers, and transporters, which dramatically and selectively increase
permeability of the membrane for different ions. The relatively high membrane permeability for
potassium ions at resting potential results from Inward-rectifier potassium ion channels, which are
open at negative voltages, and so-called leak potassium conductances such as open rectifier K+
channel (ORK+), which are locked in open state. These potassium channels should not be confused
with voltage-activated K+ channels responsible for membrane repolarization during action
potential.
A depiction of two neurons where the first upper right neuron is connected through extensions of
the cell surface of the neuron known as dendrites to the second lower left neuron. The main body of
the neuron is approximately spherical in shape where the dendrites resemble tree branches that
extend from the central body (or "tree trunk") of the neuron. An action potential from the central
body of the first cell travels along the surface of its dendrites toward the second cell. A blowup
insert in the figure shows the connection between the dendrite of the first cell to the surface of the
second cell. The end of the dendrite contains neurotransmitters stored in vesicles. These
neurotransmitters are released from the dendrites by an action potential. The neurotransmitters then
diffuse through the solution between the two cells where they bind to cell surface receptors on the
second cell.
Anatomy of a neuron
Several types of cells support an action potential, such as plant cells, muscle cells, and the
specialized cells of the heart (in which occurs the cardiac action potential). However, the main
excitable cell is the neuron, which also has the simplest mechanism for the action potential.
Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single
soma, a single axon and one or more axon terminals. The dendrite is one of the two types of
synapses, the other being the axon terminal boutons. Dendrites form protrusions in response to the
axon terminal boutons. These protrusions, or spines, are designed to capture the neurotransmitters
released by the presynaptic neuron. They have a high concentration of ligand activated channels. It
is, therefore, here where synapses from two neurons communicate with one another. These spines
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have a thin neck connecting a bulbous protrusion to the main dendrite. This ensures that changes
occurring inside the spine are less likely to affect the neighbouring spines. The dendritic spine can,
therefore, with rare exception (see LTP), act as an independent unit. The dendrites then connect
onto the soma. The soma houses the nucleus, which acts as the regulator for the neuron. Unlike the
spines, the surface of the soma is populated by voltage activated ion channels. These channels help
transmit the signals generated by the dendrites. Emerging out from the soma is the axon hillock.
This region is characterized by having an incredibly high concentration of voltage activated sodium
channels. In general, it is considered to be the spike initiation zone for action potentials. Multiple
signals generated at the spines, and transmitted by the soma all converge here. Immediately after
the axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. The
axon is insulated by a myelin sheath. Myelin is composed of Schwann cells that wrap themselves
multiple times around the axonal segment. This forms a thick fatty layer that prevents ions from
entering or escaping the axon. This insulation both prevents significant signal decay as well as
ensuring faster signal speed. This insulation, however, has the restriction that no channels can be
present on the surface of the axon. There are, therefore, regularly spaced patches of membrane,
which have no insulation. These nodes of ranvier can be considered to be 'mini axon hillocks' as
their purpose is to boost the signal in order to prevent significant signal decay. At the furthest end,
the axon loses its insulation and begins to branch into several axon terminals. These axon terminals
then end in the form the second class of synapses, axon terminal buttons. These buttons have
voltage-activated calcium channels, which come into play when signaling other neurons.
Initiation
Before considering the propagation of action potentials along axons and their termination at the
synaptic knobs, it is helpful to consider the methods by which action potentials can be initiated at
the axon hillock. The basic requirement is that the membrane voltage at the hillock be raised above
the threshold for firing. There are several ways in which this depolarization can occur.
The pre- and post-synaptic axons are separated by a short distance known as the synaptic cleft.
Neurotransmitter released by pre-synaptic axons diffuse through the synaptic clef to bind to and
open ion channels in post-synaptic axons.
When an action potential arrives at the end of the pre-synaptic axon (yellow), it causes the release
of neurotransmitter molecules that open ion channels in the post-synaptic neuron (green). The
combined excitatory and inhibitory postsynaptic potentials of such inputs can begin a new action
potential in the post-synaptic neuron.
Each action potential is followed by a refractory period, which can be divided into an absolute
refractory period, during which it is impossible to evoke another action potential, and then a
relative refractory period, during which a stronger-than-usual stimulus is required. These two
refractory periods are caused by changes in the state of sodium and potassium channel molecules.
When closing after an action potential, sodium channels enter an "inactivated" state, in which they
cannot be made to open regardless of the membrane potential—this gives rise to the absolute
refractory period. Even after a sufficient number of sodium channels have transitioned back to their
resting state, it frequently happens that a fraction of potassium channels remains open, making it
difficult for the membrane potential to depolarize, and thereby giving rise to the relative refractory
period. Because the density and subtypes of potassium channels may differ greatly between
different types of neurons, the duration of the relative refractory period is highly variable.
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The absolute refractory period is largely responsible for the unidirectional propagation of action
potentials along axons. At any given moment, the patch of axon behind the actively spiking part is
refractory, but the patch in front, not having been activated recently, is capable of being stimulated
by the depolarization from the action potential.
Propagation
The action potential generated at the axon hillock propagates as a wave along the axon. The
currents flowing inwards at a point on the axon during an action potential spread out along the
axon, and depolarize the adjacent sections of its membrane. If sufficiently strong, this
depolarization provokes a similar action potential at the neighboring membrane patches. This basic
mechanism was demonstrated by Alan Lloyd Hodgkin in 1937. After crushing or cooling nerve
segments and thus blocking the action potentials, he showed that an action potential arriving on one
side of the block could provoke another action potential on the other, provided that the blocked
segment was sufficiently short.
Once an action potential has occurred at a patch of membrane, the membrane patch needs time to
recover before it can fire again. At the molecular level, this absolute refractory period corresponds
to the time required for the voltage-activated sodium channels to recover from inactivation, i.e., to
return to their closed state. There are many types of voltage-activated potassium channels in
neurons, some of them inactivate fast (A-type currents) and some of them inactivate slowly or not
inactivate at all; this variability guarantees that there will be always an available source of current
for repolarization, even if some of the potassium channels are inactivated because of preceding
depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within
several millisecond during strong depolarization, thus making following depolarization impossible
until a substantial fraction of sodium channels is not returned to their closed state. Although it
limits the frequency of firing, the absolute refractory period ensures that the action potential moves
in only one direction along an axon. The currents flowing in due to an action potential spread out in
both directions along the axon. However, only the unfired part of the axon can respond with an
action potential; the part that has just fired is unresponsive until the action potential is safely out of
range and cannot restimulate that part. In the usual orthodromic conduction, the action potential
propagates from the axon hillock towards the synaptic knobs (the axonal termini); propagation in
the opposite direction—known as antidromic conduction—is very rare. However, if a laboratory
axon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired; then two action
potentials will be generated, one traveling towards the axon hillock and the other traveling towards
the synaptic knobs.
Axons of neurons are wrapped by several myelin sheaths, which shield the axon from extracellular
fluid. There are short gaps between the myelin sheaths known as nodes of Ranvier where the axon
is directly exposed to the surrounding extracellular fluid.
In saltatory conduction, an action potential at one node of Ranvier causes inwards currents that
depolarize the membrane at the next node, provoking a new action potential there; the action
potential appears to "hop" from node to node.
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Myelin and saltatory conduction
The evolutionary need for the fast and efficient transduction of electrical signals in nervous system
resulted in appearance of myelin sheaths around neuronal axons. Myelin is a multilamellar
membrane that enwraps the axon in segments separated by intervals known as nodes of Ranvier, is
produced by specialized cells, Schwann cells exclusively in the peripheral nervous system, and by
oligodendrocytes exclusively in the central nervous system. Myelin sheath reduces membrane
capacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast,
saltatory movement of action potentials from node to node. Myelination is found mainly in
vertebrates, but an analogous system has been discovered in a few invertebrates, such as some
species of shrimp. Not all neurons in vertebrates are myelinated; for example, axons of the neurons
comprising autonomous (vegetative) nervous system are not myelinated in general.
Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general
rule, myelination increases the conduction velocity of action potentials and makes them more
energy-efficient. Whether saltatory or not, the mean conduction velocity of an action potential
ranges from 1 m/s to over 100 m/s, and, in general, increases with axonal diameter.
Action potentials cannot propagate through the membrane in myelinated segments of the axon.
However, the current is carried by the cytoplasm, which is sufficient to depolarize the next 1 or 2
node of Ranvier. Instead, the ionic current from an action potential at one node of Ranvier provokes
another action potential at the next node; this apparent "hopping" of the action potential from node
to node is known as saltatory conduction.
Myelin has two important advantages: fast conduction speed and energy efficiency. For axons
larger than a minimum diameter (roughly 1 micrometre), myelination increases the conduction
velocity of an action potential, typically tenfold. Conversely, for a given conduction velocity,
myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentials
move at roughly the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squid
giant axon, but the frog axon has a roughly 30-fold smaller diameter and 1000-fold smaller crosssectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer ions
"leak" across the membrane, saving metabolic energy. This saving is a significant selective
advantage, since the human nervous system uses approximately 20% of the body's metabolic
energy.
The length of axons' myelinated segments is important to the success of saltatory conduction. They
should be as long as possible to maximize the speed of conduction, but not so long that the arriving
signal is too weak to provoke an action potential at the next node of Ranvier. In nature, myelinated
segments are generally long enough for the passively propagated signal to travel for at least two
nodes while retaining enough amplitude to fire an action potential at the second or third node. Thus,
the safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case of
injury. However, action potentials may end prematurely in certain places where the safety factor is
low, even in unmyelinated neurons; a common example is the branch point of an axon, where it
divides into two axons.
Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of
action potentials. The most well-known of these is multiple sclerosis, in which the breakdown of
myelin impairs coordinated movement.
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Termination
Chemical synapses
In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be released
into the synaptic cleft. Neurotransmitters are small molecules that may open ion channels in the
postsynaptic cell; most axons have the same neurotransmitter at all of their termini. The arrival of
the action potential opens voltage-sensitive calcium channels in the presynaptic membrane; the
influx of calcium causes vesicles filled with neurotransmitter to migrate to the cell's surface and
release their contents into the synaptic cleft. This complex process is inhibited by the neurotoxins
tetanospasmin and botulinum toxin, which are responsible for tetanus and botulism, respectively.
Electrical synapases are composed of protein complexes that are imbedded in both membranes of
adjacent neurons and thereby provide a direct channel for ions to flow from the cytoplasm of one
cell into an adjacent cell.
Electrical synapses between excitable cells allow ions to pass directly from one cell to another, and
are much faster than chemical synapses.
Electrical synapses
Some synapses dispense with the "middleman" of the neurotransmitter, and connect the presynaptic
and postsynaptic cells together.
When an action potential reaches such a synapse, the ionic currents flowing into the presynaptic
cell can cross the barrier of the two cell membranes and enter the postsynaptic cell through pores
known as connexins.
Thus, the ionic currents of the presynaptic action potential can directly stimulate the postsynaptic
cell. Electrical synapses allow for faster transmission because they do not require the slow diffusion
of neurotransmitters across the synaptic cleft. Hence, electrical synapses are used whenever fast
response and coordination of timing are crucial, as in escape reflexes, the retina of vertebrates, and
the heart.
Neuromuscular junctions
A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motor
neuron terminates on a muscle fiber. In such cases, the released neurotransmitter is acetylcholine,
which binds to the acetylcholine receptor, an integral membrane protein in the membrane (the
sarcolemma) of the muscle fiber. However, the acetylcholine does not remain bound; rather, it
dissociates and is hydrolyzed by the enzyme, acetylcholinesterase, located in the synapse. This
enzyme quickly reduces the stimulus to the muscle, which allows the degree and timing of
muscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase to
prevent this control, such as the nerve agents sarin and tabun, and the insecticides diazinon and
malathion.
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Method and device for evaluating nerve impulse propagation velocity and latency of
electrodermal reflexes
The method and reactometric device provide for separate or simultaneous evaluation of latency and
electrodermal reflex propagation speed through postganglionic sympathetic nerve fibers.
Evaluation is carried out by help of electronic interval counting devices and yields certain
correlations enabling differentiation between the central and peripheral neurovegetative fatigue as
well as intoxication phenomena of peripheral vegetative fibers. Evaluations are conducted through
two electrodes located on the same innervation area, i.e. on the longitudinal axis of palm, the
electrodes being spaced by a known distance which is considered in the evaluation of electrodermal
reflex propagation. The first electrode intercepts the electrodermal reflex used in the evaluation of
latency.
Electrical processes involved in the encoding of nerve impulses.
A mechanism for impulse encoding is advanced for those neurones whose impulse trigger zone
membrane is more excitable than the general axonal membrane. Electrical communication between
an electrotonically small patch of highly excitable membrane and neighboring membrane places the
control of membrane potential - in varying degree - to the larger membrane area throughout the
interspike intervals. That control is relinquished to the trigger membrane near the time of action
potential initiation in a natural fashion. Model calculations demonstrate that this mechanism can
lead to a dramatic lowering of the minimum stable firing frequency of tonic neurons, and,
additionally influence the shape of the stimulus - versus - impulse frequency curve. The results are
compared with the behavior of the slowly adapting stretch receptor neuron of the crayfish.
All-or-none law
The all-or-none law is the principle that the strength by which a nerve or muscle fiber responds to
a stimulus is not dependent on the strength of the stimulus. If the stimulus is any strength above
threshold, the nerve or muscle fiber will give a complete response or otherwise no response at all.
It was first established by the American physiologist Henry Pickering Bowditch in 1871 for the
contraction of heart muscle. According to him, describing the relation of response to stimulus,
“An induction shock produces a contraction or fails to do so according to its strength; if it does so
at all, it produces the greatest contraction that can be produced by any strength of stimulus in the
condition of the muscle at the time.”
The individual fibers of both skeletal muscle and nerve respond to stimulation according to the allor-none principle.
Relationship between stimulus and response
The magnitude of the spike potential set up in any single nerve fiber is independent of the strength
of the exciting stimulus, provided the latter is adequate. An electrical stimulus below threshold
strength fails to elicit a propagated spike potential. If it is of threshold strength or over, a spike
(representing a nervous impulse) of maximum magnitude is set up. Either the single fiber does not
respond with spike production, or it responds to the utmost of its ability under the conditions at the
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moment. This property of the single nerve fiber is termed the all-or-none relationship. It should be
emphasized relationship applies only to the unit of tissue, as well as to skeletal muscle units (the
unit being the individual muscle fiber) and to the heart(the unit being the entire auricles or the
entire ventricles).
Stimuli too weak to produce a spike do, however, set up a local electrotonus, the magnitude of the
electronic potential progressively increasing with the strength of the stimulus, until a spike is
generated.cellular reproduction is when a a neuron sends electro chemical waves down the spinal
cord This demonstrates the all-or-none relationship in spike production.
The above account deals with the response of a single nerve fiber. If a nerve trunk is stimulated,
then as the exciting stimulus is progressively increased above threshold, a larger number of fibers
respond. The minimal effective (i.e. threshold) stimulus is adequate only for fibers of high
excitability, but a stronger stimulus excites all the nerve fibers. Increasing the stimulus further does
increase the response of whole nerve.
Heart muscle is excitable, i.e. it responds to external stimuli by contracting. If the external stimulus
is too weak, no response is obtained; if the stimulus is adequate, the heart responds to the best of its
ability. Accordingly, the auricles or ventricles behave as a single unit, so that an adequate stimulus
normally produces a full contraction of either the auricles or ventricles. The force of the contraction
obtained depends on the state in which the muscles fibers find themselves. In the case of muscle
fibers, the individual muscle fiber does not respond at all if the stimulus is too weak. However, it
responds maximally when the stimulus rises to threshold. The contraction is not increased if the
stimulus strength is further raise. Stronger stimuli bring more muscle fibers into action and thus the
tension of a muscle increases as the strength of the stimulus applied to it rises.
Resting potential- Chemical Characteristics
The relatively static membrane potential of quiescent cells is called the resting membrane
potential (or resting voltage), as opposed to the specific dynamic electrochemical phenomenona
called action potential and graded membrane potential.
Apart from the latter two, which occur in excitable cells (neurons, muscles, and some secretory
cells in glands), membrane voltage in the majority of not-excitable cells can also undergo changes
in response to environmental or intracellular stimuli [citation needed]. In principle, there is no difference
between resting membrane potential and dynamic voltage changes like action potential from
biophysical point of view: all these phenomena are caused by specific changes in membrane
permeabilities for potassium, sodium, calcium, and chloride, which in turn result from concerted
changes in functional activity of various ion channels, ion transporters, and exchangers.
Conventionally, resting membrane potential can be defined as a relatively stable, ground value of
transmembrane voltage in animal and plant cells.
Any voltage is a difference in electric potential between two points - for example, the separation of
positive and negative electric charges on opposite sides of a resistive barrier. The typical resting
membrane potential of a cell arises from the separation of potassium ions from intracellular,
relatively immobile anions across the membrane of the cell. Because the membrane permeability
for potassium is much higher than that for other ions (disregarding voltage-gated channels at this
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stage), and because of the strong chemical gradient for potassium, potassium ions flow from the
cytosol into the extracellular space carrying out positive charge, until their movement is balanced
by build-up of negative charge on the inner surface of the membrane. Again, because of the high
relative permeability for potassium, the resulting membrane potential is almost always close to the
potassium reversal potential. But in order for this process to occur, a concentration gradient of
potassium ions must first be set up. This work is done by the ion pumps/transporters and/or
exchangers and generally is powered by ATP.
In the case of the resting membrane potential across an animal cell's plasma membrane, potassium
(and sodium) gradients are established by the Na+/K+-ATPase (sodium-potassium pump) which
transports 2 potassium ions inside and 3 sodium ions outside at the cost of 1 ATP molecule. In
other cases, for example, a membrane potential may be established by acidification of the inside of
a membranous compartment (such as the proton pump that generates membrane potential across
synaptic vesicle membranes).
Electroneutrality
In most quantitative treatments of membrane potential, such as the derivation of Goldman equation,
electroneutrality is assumed; that is, that there is no measurable charge excess in any side of the
membrane. So, although there is an electric potential across the membrane due to charge separation,
there is no actual measurable difference in the global concentration of positive and negative ions
across the membrane (as it is estimated below), that is, there is no actual measurable charge excess
in either side. That occurs because the effect of charge on electrochemical potential is hugely
greater than the effect of concentration so an undetectable change in concentration creates a great
change on electric potential.
Generation of the resting potential
Cell membranes are typically permeable to only a subset of ionic species. These species usually
include potassium ions, chloride ions, bicarbonate ions, and others. To simplify the description of
the ionic basis of the resting membrane potential, it is most useful to consider only one ionic
species at first, and consider the others later. Since trans-plasma-membrane potentials are almost
always determined primarily by potassium permeability, that is where to start.
The resting voltage is the result of several ion-translocating enzymes (uniporters, cotransporters,
and pumps) in the plasma membrane, steadily operating in parallel, whereby each ion-translocator
has its characteristic electromotive force (= reversal potential = 'equilibrium voltage'), depending on
the particular substrate concentrations inside and outside (internal ATP included in case of some
pumps). H+ exporting ATPase render the membrane voltage in plants and fungi much more
negative than in the more extensively investigated animal cells, where the resting voltage is mainly
determined by selective ion channels.
In most neurons the resting potential has a value of approximately -70 mV. The resting potential is
mostly determined by the concentrations of the ions in the fluids on both sides of the cell membrane
and the ion transport proteins that are in the cell membrane. How the concentrations of ions and the
membrane transport proteins influence the value of the resting potential is outlined below.
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The resting potential of a cell can be most thoroughly understood by thinking of it in terms of
equilibrium potentials. In the example diagram here, the model cell was given only one permeant
ion (potassium). In this case, the resting potential of this cell would be the same as the equilibrium
potential for potassium.
However, a real cell is more complicated, having permeabilities to many ions, each of which
contributes to the resting potential. To understand better, consider a cell with only two permeant
ions, potassium and sodium. Consider a case where these two ions have equal concentration
gradients directed in opposite directions, and that the membrane permeabilities to both ions are
equal. K+ leaving the cell will tend to drag the membrane potential toward EK. Na+ entering the cell
will tend to drag the membrane potential toward the reversal potential for sodium ENa. Since the
permeabilities to both ions were set to be equal, the membrane potential will, at the end of the
Na+/K+ tug-of-war, end up halfway between ENa and EK. As ENa and EK were equal but of opposite
signs, halfway in between is zero, meaning that the membrane will rest at 0 mV.
Note that even though the membrane potential at 0 mV is stable, it is not an equilibrium condition
because neither of the contributing ions are in equilibrium. Ions diffuse down their electrochemical
gradients through ion channels, but the membrane potential is upheld by continual K + influx and
Na+ efflux via ion transporters. Such situation with similar permeabilities for counter-acting ions,
like potassium and sodium in animal cells, can be extremely costly for the cell if these
permeabilities are relatively large, as it takes a lot of ATP energy to pump the ions back. Because
no real cell can afford such equal and large ionic permeabilities at rest, resting potential of animal
cells is determined by predominant high permeability to potassium and adjusted to the required
value by modulating sodium and chloride permeabilities and gradients.

In a healthy animal cell Na+ permeability is about 5% of the K permeability or even less,
whereas the respective reversal potentials are +60 mV for sodium (ENa)and -80 mV for
potassium (EK). Thus the membrane potential will not be right at EK, but rather depolarized
from EK by an amount of approximately 5% of the 140 mV difference
Membrane transport proteins
For determination of membrane potentials, the two most important types of membrane ion transport
proteins are ion channels and ion transporters. Ion channel proteins create paths across cell
membranes through which ions can passively diffuse without direct expenditure of metabolic
energy. They have selectivity for certain ions, thus, there are potassium-, chloride-, and sodiumselective ion channels. Different cells and even different parts of one cell (dendrites, cell bodies,
nodes of Ranvier) will have different amounts of various ion transport proteins. Typically, the
amount of certain potassium channels is most important for control of the resting potential (see
below). Some ion pumps such as the Na+/K+-ATPase are electrogenic, that is, they produce charge
imbalance across the cell membrane and can also contribute directly to the membrane potential.
Most pumps use metabolic energy (ATP) to function.
Equilibrium potentials
For most animal cells potassium ions (K+) are the most important for the resting potential. Due to
the active transport of potassium ions, the concentration of potassium is higher inside cells than
outside. Most cells have potassium-selective ion channel proteins that remain open all the time.
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There will be net movement of positively-charged potassium ions through these potassium channels
with a resulting accumulation of excess negative charge inside of the cell. The outward movement
of positively-charged potassium ions is due to random molecular motion (diffusion) and continues
until enough excess negative charge accumulates inside the cell to form a membrane potential
which can balance the difference in concentration of potassium between inside and outside the cell.
"Balance" means that the electrical force (potential) that results from the build-up of ionic charge,
and which impedes outward diffusion, increases until it is equal in magnitude but opposite in
direction to the tendency for outward diffusive movement of potassium. This balance point is an
equilibrium potential as the net transmembrane flux (or current) of K+ is zero. The equilibrium
potential for a given ion depends only upon the concentrations on either side of the membrane and
the temperature. It can be calculated using the Nernst equation.
Potassium equilibrium potentials of around -80 millivolts (inside negative) are common.
Differences are observed in different species, different tissues within the same animal, and the same
tissues under different environmental conditions. Applying the Nernst Equation above, one may
account for these differences by changes in relative K+ concentration or differences in temperature.
Resting potentials
The resting membrane potential is not an equilibrium potential as it relies on the constant
expenditure of energy (for ionic pumps as mentioned above) for its maintenance. It is a dynamic
diffusion potential that takes mechanism into account—wholly unlike the equilibrium potential,
which is true no matter the nature of the system under consideration. The resting membrane
potential is dominated by the ionic species in the system that has the greatest conductance across
the membrane. For most cells this is potassium. As potassium is also the ion with the most negative
equilibrium potential, usually the resting potential can be no more negative than the potassium
equilibrium potential. The resting potential can be calculated with the Goldman-Hodgkin-Katz
voltage equation using the concentrations of ions as for the equilibrium potential while also
including the relative permeabilities, or conductances, of each ionic species. Under normal
conditions, it is safe to assume that only potassium, sodium (Na+) and chloride (Cl-) ions play large
roles for the resting potential.
Measuring resting potentials
In some cells, the membrane potential is always changing (such as cardiac pacemaker cells). For
such cells there is never any “rest” and the “resting potential” is a theoretical concept. Other cells
with little in the way of membrane transport functions that change with time have a resting
membrane potential that can be measured by inserting an electrode into the cell . Transmembrane
potentials can also be measured optically with dyes that change their optical properties according to
the membrane potential.
Summary of resting potential values in different types of cells
The resting membrane potential in different cell types are approximately:




Skeletal muscle cells: −95 mV
Smooth muscle cells: -50mV
Astroglia: -80/-90mV
Neurons: -70mV
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Generator and Graded potentials
Differences in concentration of ions on opposite sides of a cellular membrane produce a voltage
difference called the membrane potential. The largest contributions usually come from sodium
(Na+) and chloride (Cl–) ions which have high concentrations in the extracellular region, and
potassium (K+) ions, which along with large protein anions have high concentrations in the
intracellular region. Calcium ions, which sometimes play an important role, are not shown.
Membrane potential (or transmembrane potential) is the difference in voltage (or electrical
potential difference) between the interior and exterior of a cell (Vinterior − Vexterior). All animal cells
are surrounded by a plasma membrane composed of a lipid bilayer with many diverse protein
assemblages embedded in it. The fluid on both sides of the membrane contains high concentrations
of mobile ions, of which sodium (Na+), potassium (K+), chloride (Cl–), and calcium (Ca2+) are the
most important. The membrane potential arises from the interaction of ion channels and ion pumps
embedded in the membrane, which maintain different ion concentrations on the intracellular and
extracellular sides of the membrane.
The membrane potential has two basic functions. First, it allows a cell to function as a battery,
providing power to operate a variety of "molecular devices" embedded in the membrane. Second,
in electrically excitable cells such as neurons, it is used for transmitting signals between different
parts of a cell. Opening or closing of ion channels at one point in the membrane produces a local
change in the membrane potential, which causes electric current to flow rapidly to other points in
the membrane.
In non-excitable cells, and in excitable cells in their baseline states, the membrane potential is held
at a relatively stable value, called the resting potential. For neurons, typical values of the resting
potential range from -70 to -80 millivolts; that is, the interior of a cell has a negative baseline
voltage of a bit less than one tenth of a volt. Opening and closing of ion channels can induce a
departure from the resting potential, called a depolarization if the interior voltage rises (say from 70 mV to -65 mV), or a hyperpolarization if the interior voltage becomes more negative (changing
from -70 mV to -80 mV, for example). In excitable cells, a sufficiently large depolarization can
evoke a short-lasting all-or-nothing event called an action potential, in which the membrane
potential very rapidly undergoes a large change, often briefly reversing its sign. Action potentials
are generated by special types of voltage-dependent ion channels.
In neurons, the factors that influence the membrane potential are diverse. They include numerous
types of ion channels, some that are chemically gated and some that are voltage-gated. Because
voltage-dependent ion channels are controlled by the membrane potential, while the membrane
potential itself is partly controlled by these same ion channels, feedback loops arise which allow for
complex temporal dynamics, including oscillations and regenerative events such as action
potentials.
Physical basis
The membrane potential in a cell derives ultimately from two factors: electrical force and diffusion.
Electrical force arises from the mutual attraction between particles with opposite electrical charges
(positive and negative) and the mutual repulsion between particles with the same type of charge
(both positive or both negative). Diffusion arises from the statistical tendency of particles to
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redistribute from regions where they are highly concentrated to regions where the concentration is
low.
Voltage
Voltage, which is synonymous with electrical potential, is relatively simple to define
mathematically, but not easy to explain concretely in a non-mathematical way. Intuitively, voltage
is the ability to drive an electrical current. If a voltage source such as a battery is placed in an
electrical circuit, the higher the voltage of the source, the greater the amount of current that it will
drive. In a functioning circuit, each point can be assigned a voltage level—the voltage difference
between any two points determines the amount of current that would flow through a wire hooked
directly from one point to the other. In practical electronics, the voltage difference between two
points can be measured by connecting them to the two leads of a volt meter (voltmeter).
The functional significance of voltage lies only in voltage differences—the absolute value of
voltage has no significance. A volt meter can measure the voltage difference between two locations
in a circuit, but there is no instrument that can measure the voltage at a single point: the concept has
no meaning. It is conventional in electronics to assign a voltage of zero to some arbitrarily chosen
element of the circuit, and then assign voltages for other elements on the basis of the measured or
calculated voltage differences, but there is no significance in which element is chosen as the zero
point—the function of a circuit depends only on the differences, not on voltages per se.
The same principle applies to voltage in cell biology. In electrically active tissue, the voltage
difference between any two points can be measured by inserting an electrode at each point and
connecting both electrodes to the leads of a volt meter. There is no way, however, to measure the
voltage of a single point. Thus, a statement that the voltage difference across the membrane of a
cell is 60 millivolts can be verified by placing electrodes inside and outside the cell—but whether
the exterior is assigned a voltage of 60 mV and the interior 0 mV, or the exterior is assigned a
voltage of 0 mV and the interior -60 mV, has no significance; only the difference between the two
matters, not the absolute number assigned to either.
In mathematical terms, the definition of voltage begins with the concept of an electric field E, a
vector field assigning a magnitude and direction to each point in space. In many situations, the
electric field is a conservative field, which means that it can be expressed as the gradient of a scalar
function V, that is, E = ∇V. This scalar field V is referred to as the voltage distribution. Note that the
definition allows for an arbitrary constant of integration—this is why absolute values of voltage are
not meaningful. In general electric fields can only be treated as conservative if magnetic fields do
not significantly influence them, but this condition usually applies well to biological tissue.
Because the electric field is the gradient of the voltage distribution, rapid changes in voltage within
a small region imply a strong electric field; conversely, if the voltage remains approximately the
same over a large region, the electric fields in that region must be weak. A strong electric field,
equivalent to a strong voltage gradient, implies that a strong force is exerted on any charged
particles that lie within the region.
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Salts and ions in an aqueous medium
The fluid both inside and outside of animal cells (intracellular and extracellular) contains a high
concentration of dissolved salts. When salts dissolve in water, they break apart into ions—for
example sodium chloride (NaCl) breaks up almost entirely into positively charged sodium ions
(Na+) and negatively charged chloride (Cl–) ions. Small ions such as sodium (Na+), potassium (K+),
calcium (Ca++), and chloride (Cl–) are present in high concentrations, and are capable of diffusing
freely from place to place, unless some type of barrier impedes them.
Plasma membrane
The cell membrane, also called the plasma membrane or plasmalemma, is a semipermeable lipid
bilayer common to all living cells. It contains a variety of biological molecules, primarily proteins
and lipids, which are involved in a vast array of cellular processes.
Every animal cell is enclosed in a plasma membrane, which has the structure of a lipid bilayer with
many types of large molecules embedded in it. Because it is made of lipid molecules, the plasma
membrane intrinsically has a high electrical resistivity, in other words a low intrinsic permeability
to ions. However, some of the molecules embedded in the membrane are capable either of actively
transporting ions from one side of the membrane to the other, or of providing channels through
which they can move.
In electrical terminology, the plasma membrane functions as a combined resistor and capacitor.
Resistance arises from the fact that the membrane impedes the movement of charges across it.
Capacitance arises from the fact that the lipid bilayer is so thin that an accumulation of charged
particles on one side gives rise to an electrical force that pulls oppositely-charged particles toward
the other side. The capacitance of the membrane is relatively unaffected by the molecules that are
embedded in it, so it has a more or less invariant value estimated at about 2 µF/cm 2 (the total
capacitance of a patch of membrane is proportional to its area). The conductance of a pure lipid
bilayer is so low, on the other hand, that in biological situations it is always dominated by the
conductance of alternative pathways provided by embedded molecules. Thus the capacitance of the
membrane is more or less fixed, but the resistance is highly variable.
The thickness of a plasma membrane is estimated to be about 7-8 nanometers. Because the
membrane is so thin, it does not take a very large transmembrane voltage to create a strong electric
field within it. Typical membrane potentials in animal cells are on the order of 100 millivolts (that
is, one tenth of a volt), but calculations show that this generates an electric field close to the
maximum that the membrane can sustain—it has been calculated that a voltage difference much
larger than 200 millivolts could cause dielectric breakdown, that is, arcing across the membrane.
Facilitated diffusion and transport
The resistance of a pure lipid bilayer to the passage of ions across it is very high, but structures
embedded in the membrane can greatly enhance ion movement, either actively or passively, via
mechanisms called facilitated transport and facilitated diffusion. The two types of structure that
play the largest roles are ion channels and ion pumps, both usually formed from assemblages of
protein molecules. Ion channels provide passageways through which ions can move. In most cases
an ion channel is only permeable to specific types of ions (for example sodium and potassium but
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not chloride or calcium), and sometimes the permeability varies depending on the direction of ion
movement. Ion pumps, also known as ion transporters or carrier proteins, actively transport specific
types of ions from one side of the membrane to the other, sometimes using energy derived from
metabolic processes to do so.
Ion pumps
A major contribution to establishing the membrane potential is made by the sodium-potassium
exchange pump. This is a complex of proteins embedded in the membrane that derives energy from
ATP in order to transport sodium and potassium ions across the membrane. On each cycle, the
pump exchanges three Na+ ions from the intracellular space for two K+ ions from the extracellular
space. If the numbers of each type of ion were equal, the pump would be electrically neutral, but
because of the three-for-two exchange, it gives a net movement of one positive charge from
intracellular to extracellular for each cycle, thereby contributing to a positive voltage difference.
The pump has three effects: (1) it makes the sodium concentration high in the extracellular space
and low in the intracellular space; (2) it makes the potassium concentration high in the intracellular
space and low in the extracellular space; (3) it gives the extracellular space a positive voltage with
respect to the intracellular space.
The sodium-potassium exchange pump is relatively slow in operation. If a cell were initialized with
equal concentrations of sodium and potassium everywhere, it would take hours for the pump to
establish equilibrium. The pump operates constantly, but becomes progressively less efficient as the
concentrations of sodium and potassium available for pumping are reduced.
Another functionally important ion pump is the sodium-calcium exchanger. This pump operates in
a conceptually similar way to the sodium-potassium pump, except that in each cycle it exchanges
three Na+ from the extracellular space for one Ca++ from the intracellular space. Because the net
flow of charge is inward, this pump runs "downhill", effectively, and therefore does not require any
energy source except the membrane voltage. Its most important effect is to pump calcium
outward—it also allows an inward flow of sodium, thereby counteracting the sodium-potassium
pump, but because overall sodium and potassium concentrations are much higher than calcium
concentrations, this effect is relatively unimportant. The net result of the sodium-calcium exchanger
is that in the resting state, intracellular calcium concentrations become very low.
Ion channels
As explained above, a pure lipid bilayer has a very low permeability to ions of any type. However,
animal cell membranes contain a very diverse set of ion channels, which are protein structures
embedded in the membrane that allow passage of specific types of ions under specific conditions.
These can be divided into three types: leakage channels, ligand-gated channels, and voltagedependent channels. This categorization is not exhaustive—it leaves out sensory receptors, many of
which depend on ion channels that are activated by physical stimuli such as light, temperature, or
stretching.
Leakage channels
Leakage channels are the simplest type, in that their permeability is more or less constant. The
types of leakage channels that have the greatest significance in neurons are potassium and chloride
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channels. It should be noted that even these are not perfectly constant in their properties: first, most
of them are voltage-dependent in the sense that they conduct better in one direction than the other
(in other words, they are rectifiers); second, some of them are capable of being shut off by chemical
ligands even though they do not require ligands in order to operate.
Ligand-gated channels
Ligand-gated ion channels are channels whose permeability is greatly increased when some type of
chemical ligand binds to the protein structure. Animal cells contain hundreds, if not thousands, of
types of these. A large subset function as neurotransmitter receptors—they occur at postsynaptic
sites, and the chemical ligand that gates them is released by the presynaptic axon terminal. One
example of this type is the AMPA receptor, a receptor for the neurotransmitter glutamate that when
activated allows passage of sodium and potassium ions. Another example is the GABAA receptor, a
receptor for the neurotransmitter GABA that when activated allows passage of chloride ions.
Neurotransmitter receptors are activated by ligands that appear in the extracellular area, but there
are other types of ligand-gated channels that are controlled by interactions on the intracellular side.
Voltage-dependent channels
Voltage-gated ion channels, also known as voltage dependent, are channels whose permeability is
influenced by the membrane potential. They form another very large group, with each member
having a particular ion selectivity and a particular voltage dependence. Many are also timedependent—in other words, they do not respond immediately to a voltage change, but only after a
delay.
One of the most important members of this group is a type of voltage-gated sodium channel that
underlies action potentials—these are sometimes called Hodgkin-Huxley sodium channels because
they were initially characterized by Alan Lloyd Hodgkin and Andrew Huxley in their Nobel Prizewinning studies of the physiology of the action potential. The channel is closed at the resting
voltage level, but opens abruptly when the voltage exceeds a certain threshold, allowing a large
influx of sodium ions that produces a very rapid change in the membrane potential. Recovery from
an action potential is partly dependent on a type of voltage-gated potassium channel which is closed
at the resting voltage level but opens as a consequence of the large voltage change produced during
the action potential.
Some voltage-dependent ion channels are also at the same time ligand-gated. One of the best
known of these is the NMDA receptor, a type of calcium channel that is gated by the
neurotransmitter glutamate but also requires the membrane potential to be elevated substantially
above baseline in order to open.
Reversal potential
The reversal potential (or equilibrium potential) of an ion is the value of transmembrane voltage at
which diffusive and electrical forces counterbalance, so that there is no net ion flow across the
membrane. This means that the transmembrane voltage exactly opposes the force of diffusion of the
ion , such that the net current of the ion across the membrane is zero and unchanging. The reversal
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potential is important because it gives the voltage that acts on channels permeable to that ion—in
other words, it gives the voltage that the
Equivalent circuit
Electrophysiologists model the effects of ionic concentration differences, ion channels, and
membrane capacitance in terms of an equivalent circuit, which is intended to represent the electrical
properties of a small patch of membrane. The equivalent circuit consists of a capacitor in parallel
with four pathways each consisting of a battery in series with a variable conductance. The
capacitance is determined by the properties of the lipid bilayer, and is taken to be fixed. Each of the
four parallel pathways comes from one of the principal ions, sodium, potassium, chloride, and
calcium. The voltage of each ionic pathway is determined by the concentrations of the ion on each
side of the membrane; see the Reversal potential section below. The conductance of each ionic
pathway at any point in time is determined by the states of all the ion channels that are potentially
permeable to that ion, including leakage channels, ligand-gated channels, and voltage-dependent
channels.
Reduced circuit obtained by combining the ion-specific pathways using the Goldman equation
For fixed ion concentrations and fixed values of ion channel conductance, the equivalent circuit can
be further reduced, using the Goldman equation as described below, to a circuit containing a
capacitance in parallel with a battery and conductance. Electrically this is a type of RC circuit
(resistance-capacitance circuit), and its electrical properties are very simple. Starting from any
initial state, the current flowing across either the conductance or capacitance decays with an
exponential time course, with a time constant of τ = RC, where C is the capacitance of the
membrane patch, and R = 1/gnet is the net resistance. For realistic situations the time constant
usually lies in the 1—100 millisecond range. In most cases changes in the conductance of ion
channels occur on a faster time scale, so an RC circuit is not a good approximation; however the
differential commonly equation used to model a membrane patch is a modified version of the RC
circuit equation.
Graded potentials
As explained above, the membrane potential at any point in a cell's membrane is determined by the
ion concentration differences between the intracellular and extracellular areas, and by the
permeability of the membrane to each type of ion. The ion concentrations do not normally change
very quickly (with the exception of calcium, where the baseline intracellular concentration is so low
that even a small inflow may increase it by orders of magnitude), but the permeabilities can change
in a fraction of a millisecond, as a result of activation of ligand-gated or voltage-gated ion channels.
The change in membrane potential can be large or small, depending on how many ion channels are
activated and what type they are. Changes of this type are referred to as graded potentials, in
contrast to action potentials, which have a fixed amplitude and time course.
As can be derived from the Goldman equation shown above, the effect of increasing the
permeability for a particular type of ion is to shift the membrane potential toward the reversal
potential for that ion. Thus, opening sodium channels pulls the membrane potential toward the
sodium reversal potential, usually around +100 mV. Opening potassium channels pulls the
membrane potential toward about -90 mV; opening chloride channels pulls it toward about -70 mV.
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Because -90 to +100 mV is the full operating range of membrane potential, the effect is that sodium
channels always pull the membrane potential up, potassium channels pull it down, and chloride
channels pull it toward the resting potential.
Graded membrane potentials are particularly important in neurons, where they are produced by
synapses—a temporary rise or fall in membrane potential produced by activation of a synapse is
called a postsynaptic potential. Neurotransmitters that act to open sodium channels cause the
membrane potential to rise, while neurotransmitters that act on potassium channels cause it to fall.
Because the membrane potential in a neuron must rise past the threshold value to produce an action
potential, a rise in membrane potential is excitatory, while a fall is inhibitory. Thus
neurotransmitters that act to open sodium channels produce a so-called excitatory postsynaptic
potential, or EPSP, whereas neurotransmitters that act to open potassium channels produce an
inhibitory postsynaptic potential, or IPSP. When multiple types of channels are open within the
same time period, their postsynaptic potentials summate.
All other values of membrane potential
From the viewpoint of biophysics, there is nothing particularly special about the resting membrane
potential. It is merely the membrane potential that results from the membrane permeabilities that
predominate when the cell is resting. The above equation of weighted averages always applies, but
the following approach may be easier to visualize. At any given moment, there are two factors for
an ion that determine how much influence that ion will have over the membrane potential of a cell.
1. That ion's driving force and,
2. That ion's permeability
Intuitively, this is easy to understand. If the driving force is high, then the ion is being "pushed"
across the membrane hard (more correctly stated: it is diffusing in one direction faster than the
other). If the permeability is high, it will be easier for the ion to diffuse across the membrane. But
what are 'driving force' and 'permeability'?

Driving force: the driving force is the net electrical force available to move that ion across
the membrane. It is calculated as the difference between the voltage that the ion "wants" to
be at (its equilibrium potential) and the actual membrane potential (Em). So formally, the
driving force for an ion = Em - Eion

For example, at our earlier calculated resting potential of −73 mV, the driving force on
potassium is 7 mV (−73 mV) − (−80 mV) = 7 mV. The driving force on sodium would be
(−73 mV) − (60 mV) = −133 mV.

Permeability: is simply a measure of how easily an ion can cross the membrane. It is
normally measured as the (electrical) conductance and the unit, siemens, corresponds to 1
C·s−1·V−1, that is one charge per second per volt of potential.
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So in a resting membrane, while the driving force for potassium is low, its permeability is very
high. Sodium has a huge driving force, but almost no resting permeability. In this case, the math
tells us that potassium carries about 20 times more current than sodium, and thus has 20 times more
influence over Em than does sodium.
However, consider another case—the peak of the action potential. Here permeability to Na is high
and K permeability is relatively low. Thus the membrane moves to near ENa and far from EK.
The more ions are permeant, the more complicated it becomes to predict the membrane potential.
However, this can be done using the Goldman-Hodgkin-Katz equation or the weighted means
equation. By simply plugging in the concentration gradients and the permeabilities of the ions at
any instant in time, one can determine the membrane potential at that moment. What the GHK
equations says, basically, is that at any time, the value of the membrane potential will be a weighted
average of the equilibrium potentials of all permeant ions. The "weighting" is the ions relative
permeability across the membrane.
Effects and implications
While cells expend energy to transport ions and establish a transmembrane potential, they use this
potential in turn to transport other ions and metabolites such as sugar. The transmembrane potential
of the mitochondria drives the production of ATP, which is the common currency of biological
energy.
Cells may draw on the energy they store in the resting potential to drive action potentials or other
forms of excitation. These changes in the membrane potential enable communication with other
cells (as with action potentials) or initiate changes inside the cell, which happens in an egg when it
is fertilized by a sperm.
In neuronal cells, an action potential begins with a rush of sodium ions into the cell through sodium
channels, resulting in depolarization, while recovery involves an outward rush of potassium
through potassium channels. Both these fluxes occur by passive diffusion.
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or
chemical signal to another cell. The word "synapse" comes from "synaptein", which Sir Charles
Scott Sherrington and colleagues coined from the Greek "syn-" ("together") and "haptein" ("to
clasp").
Synapses are essential to neuronal function: neurons are cells that are specialized to pass signals to
individual target cells, and synapses are the means by which they do so. At a synapse, the plasma
membrane of the signal-passing neuron (the presynaptic neuron) comes into close apposition with
the membrane of the target (postsynaptic) cell. Both the presynaptic and postsynaptic sites contain
extensive arrays of molecular machinery that link the two membranes together and carry out the
signaling process. In many synapses, the presynaptic part is located on an axon, but some
presynaptic sites are located on a dendrite or soma.
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There are two fundamentally different types of synapse:

In a chemical synapse, the presynaptic neuron releases a chemical called a neurotransmitter
that binds to receptors located in the postsynaptic cell, usually embedded in the plasma
membrane. Binding of the neurotransmitter to a receptor can affect the postsynaptic cell in a
wide variety of ways.

In an electrical synapse, the presynaptic and postsynaptic cell membranes are connected by
channels that are capable of passing electrical current, causing voltage changes in the
presynaptic cell to induce voltage changes in the postsynaptic cell.
Neurotransmitter
Neurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cell
across the synapse. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the
membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they
bind to receptors in the membrane on the postsynaptic side of the synapse. Release of
neurotransmitters usually follows arrival of an action potential at the synapse, but may follow
graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation.
Discovery
In the early 20th century, scientists assumed that synaptic communication was electrical. However,
through the careful histological examinations of Ramón y Cajal (1852–1934), a 20 to 40 nm gap
between neurons, known today as the synaptic cleft, was discovered and cast doubt on the
possibility of electrical transmission. In 1921, German pharmacologist Otto Loewi (1873–1961)
confirmed the notion that neurons communicate by releasing chemicals. Through a series of
experiments involving the vagus nerves of frogs, Loewi was able to manually control the heart rate
of frogs by controlling the amount of saline solution present around the vagus nerve. Upon
completion of this experiment, Loewi asserted that neurons do not communicate with electric
signals but rather through the change in chemical concentrations. Furthermore, Otto Loewi is
accredited with discovering acetylcholine—the first known neurotransmitter.
Identifying neurotransmitters
Some of the properties that define a chemical as a neurotransmitter are difficult to test
experimentally. For example, it is easy using an electron microscope to recognize vesicles on the
presynaptic side of a synapse, but it may not be easy to determine directly what chemical is packed
into them. The difficulties led to many historical controversies over whether a given chemical was
or was not clearly established as a transmitter. In an effort to give some structure to the arguments,
neurochemists worked out a set of experimentally tractable rules. According to the prevailing
beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following
conditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of the
synapse.

The chemical is present in the presynaptic element.
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
It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic
neuron;

There are postsynaptic receptors and the chemical is able to bind to them.

A biochemical mechanism for inactivation is present.
Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the
importance of these rules. A series of experiments that may have taken several years in the 1960s
can now be done, with much better precision, in a few months. Thus, it is unusual nowadays for the
identification of a chemical as a neurotransmitter to remain controversial for very long.
Types of neurotransmitters
There are many different ways to classify neurotransmitters. Dividing them into amino acids,
peptides, and monoamines is sufficient for some classification purposes.
Major neurotransmitters:

Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine

Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine
(adrenaline), histamine, serotonin (SE, 5-HT), melatonin

Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly.
Many of these are "co-released" along with a small-molecule transmitter, but in some cases a
peptide is the primary transmitter at a synapse.
Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, as
are some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). These are not
classical neurotransmitters by the strictest definition, however, because although they have all been
shown experimentally to be released by presynaptic terminals in an activity-dependent way, they
are not packaged into vesicles.
By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the
synapses in the human brain. The next most prevalent is GABA, which is inhibitory at more than
90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewer
synapses, they may be very important functionally—the great majority of psychoactive drugs exert
their effects by altering the actions of some neurotransmitter systems, often acting through
transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamine
exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects
primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.
Excitatory and inhibitory
Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct
effect of a neurotransmitter is to activate one or more types of receptors. The effect on the
postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for
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some neurotransmitters (for example, glutamate), the most important receptors all have excitatory
effects: that is, they increase the probability that the target cell will fire an action potential. For
other neurotransmitters (such as GABA), the most important receptors all have inhibitory effects.
There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and
inhibitory receptors exist; and there are some types of receptors that activate complex metabolic
pathways in the postsynaptic cell to produce effects that cannot appropriately be called either
excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or
inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that
this usage is seen very frequently.
Actions
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore,
the effects of a neurotransmitter system depend on the connections of the neurons that use the
transmitter, and the chemical properties of the receptors that the transmitter binds to.
Here are a few examples of important neurotransmitter actions:

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal
cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or
decreasing in strength. Modifiable synapses are thought to be the main memory-storage
elements in the brain.

GABA is used at the great majority of fast inhibitory synapses in virtually every part of the
brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.
Correspondingly glycine is the inhibitory transmitter in the spinal cord.

Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting
motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at
these synapses. Acetylcholine also operates in many regions of the brain, but using different
types of receptors.

Dopamine has a number of important functions in the brain. It plays a critical role in the
reward system, but dysfunction of the dopamine system is also implicated in Parkinson's
disease and schizophrenia.

Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine
(approximately 90%), and the remainder in central nervous system neurons. It functions to
regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle
contraction, and function of the cardiovascular system and endocrine system. It is
speculated to have a role in depression, as some depressed patients are seen to have lower
concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.

Substance P undecapeptide responsible for transmission of pain from certain sensory
neurons to the central nervous system.
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where
activation of the system affects large volumes of the brain, called volume transmission. Major
neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system,
the serotonin system and the cholinergic system.
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Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains the
complexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine back
into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap longer.
Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the
receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction
to cocaine may result from prolonged exposure to excess dopamine in the synapses, causing the
body to down-regulate some postsynaptic receptors. After the effects of the drug wear off, one
might feel depressed because of the decreased probability of the neurotransmitter binding to a
receptor. Prozac is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake of
serotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse and
allows it to remain there longer, hence potentiating the effect of naturally released serotonin.
AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine
prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B
and thus increases dopamine levels.
Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at least
in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia
nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected,
with moderate success.
A brief comparison of the major neurotransmitter systems follows:
Neurotransmitter systems
System
Origin
Effects
Noradrenaline
system
locus coeruleus

arousal
Lateral tegmental field

reward
dopamine pathways:

Dopamine system



mesocortical pathway
mesolimbic pathway
nigrostriatal pathway
tuberoinfundibular
pathway
caudal dorsal raphe nucleus
Serotonin system
rostral dorsal raphe nucleus
pontomesencephalotegmental
complex
Cholinergic system basal optic nucleus of Meynert
medial septal nucleus
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motor system, reward, cognition,
endocrine, nausea
Increase (introversion), mood, satiety,
body temperature and sleep, while
decreasing nociception.




learning
short-term memory
arousal
reward
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Common neurotransmitters
Abbreviation
Category
Name
Metabotropic
Small: Amino acids Aspartate
Neuropeptides
Small: Amino acids
Ionotropic
-
-
NNAAG
Acetylaspartylglutamate
Metabotropic
glutamate
receptors; selective
agonist of mGluR3
Glutamate
acid)
NMDA
receptor,
Metabotropic
Kainate
glutamate receptor
receptor,
AMPA receptor
(glutamic
Glu
Gamma-aminobutyric
Small: Amino acids
acid
GABA
GABAB receptor
GABAA,
GABAA-ρ
receptor
Small: Amino acids Glycine
Gly
-
Glycine
receptor
Small:
Acetylcholine
Ach
Muscarinic
acetylcholine
receptor
Nicotinic
acetylcholine
receptor
Small: Monoamine
Dopamine
(Phe/Tyr)
DA
Dopamine receptor -
Small: Monoamine Norepinephrine
(Phe/Tyr)
(noradrenaline)
NE
Adrenergic
receptor
-
Small: Monoamine
Epinephrine (adrenaline) Epi
(Phe/Tyr)
Adrenergic
receptor
-
Small: Monoamine
Octopamine
(Phe/Tyr)
-
-
Small: Monoamine
Tyramine
(Phe/Tyr)
-
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Acetylcholine
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Small: Monoamine Serotonin
(Trp)
hydroxytryptamine)
5-HT
Serotonin receptor,
5-HT3
all but 5-HT3
Small: Monoamine
Melatonin
(Trp)
Mel
Melatonin receptor -
Small: Monoamine
Histamine
(His)
H
Histamine receptor -
PP: Gastrins
Gastrin
PP: Gastrins
Cholecystokinin
(5-
-
-
CCK
Cholecystokinin
receptor
-
PP:
Vasopressin
Neurohypophyseals
AVP
Vasopressin
receptor
-
PP:
Oxytocin
Neurohypophyseals
OT
Oxytocin receptor
-
PP:
Neurophysin I
Neurohypophyseals
-
-
PP:
Neurophysin II
Neurohypophyseals
-
-
PP: Neuropeptide Y Neuropeptide Y
NY
Neuropeptide
receptor
Y
PP: Neuropeptide Y Pancreatic polypeptide
PP
-
-
PP: Neuropeptide Y Peptide YY
PYY
-
-
ACTH
Corticotropin
receptor
-
-
PP: Opioids
Corticotropin
(adrenocorticotropic
hormone)
PP: Opioids
Dynorphin
-
-
PP: Opioids
Endorphin
-
-
PP: Opioids
Enkephaline
-
-
PP: Secretins
Secretin
Secretin receptor
-
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PP: Secretins
Motilin
Motilin receptor
PP: Secretins
Glucagon
Glucagon receptor -
PP: Secretins
Vasoactive
peptide
PP: Secretins
Growth
hormoneGRF
releasing factor
-
-
PP: Somtostatins
Somatostatin
Somatostatin
receptor
-
SS: Tachykinins
Neurokinin A
-
-
SS: Tachykinins
Neurokinin B
-
-
SS: Tachykinins
Substance P
-
-
PP: Other
Bombesin
-
-
PP: Other
Gastrin releasing peptide GRP
-
-
Gas
Nitric oxide
Soluble
cyclase
intestinal
VIP
NO
-
Vasoactive
intestinal peptide receptor
guanylyl
-
Gas
Carbon monoxide
CO
-
Heme bound to
potassium
channels
Other
Anandamide
AEA
Cannabinoid
receptor
-
Other
Adenosine triphosphate
ATP
P2Y12
P2X receptor
Precursors of neurotransmitters
While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is
mixed as to whether neurotransmitter release (firing) is increased. Even with increased
neurotransmitter release, it is unclear whether this will result in a long-term increase in
neurotransmitter signal strength, since the nervous system can adapt to changes such as increased
neurotransmitter synthesis and may therefore maintain constant firing. Some neurotransmitters may
have a role in depression, and there is some evidence to suggest that intake of precursors of these
neurotransmitters may be useful in the treatment of mild and moderate depression.
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Norepinephrine precursors
For depressed patients where low activity of the neurotransmitter norepinephrine is implicated,
there is only little evidence for benefit of neurotransmitter precursor administration. Lphenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine.
These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies
suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room
for further research in this area.
Serotonin precursors
Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of
serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and
moderate depression. This conversion requires vitamin C.
5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo
and nearly as effective or of equal effectiveness to some antidepressants. Interestingly, it takes less
than 2 weeks for an antidepressant response to occur, while antidepressant drugs generally take 2–4
weeks. 5-HTP also has no significant side effects.
Administration of 5-HTP bypasses the rate-limiting step in the synthesis of serotonin from
tryptophan. Also, 5-HTP readily passes through the blood-brain barrier, and enters the central
nervous system without need of a transport molecule. Note, however, that there is some evidence to
suggest that a postsynaptic defect in serotonin utilization may be an important factor in depression,
not only insufficient serotonin.
It is important to note that not all cases of depression are caused by low levels of serotonin.
However, in the subgroup of depressed patients that are serotonin-deficient, there is strong evidence
to suggest that 5-HTP is therapeutically useful in treating depression, and more useful than Ltryptophan.
Depression does not have one cause; not all cases of depression are due to low levels of serotonin
or norepinephrine. Blood tests for the ratio of tryptophan to other amino acids, as well as red blood
cell membrane transport of these amino acids, can be predictive of whether serotonin or
norepinephrine would be of therapeutic benefit. Overall, there is evidence to suggest that
neurotransmitter precursors may be useful in the treatment of mild and moderate depression.
Degradation and elimination
Neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further
excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory
neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and recycled
by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are
able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the
kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at
regulatory points, which may be the target of the body's own regulatory system or recreational
drugs.
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Polysynaptic Reflex
A reflex action that involves an electrical impulse being transferred from a sensory neuron to a
motor neuron via at least one connecting neuron (interneuron) in the spinal cord. For example,
stimulation of pain receptors in the skin initiates a withdrawal reflex, which involves several
synapses with several motor neurons and results in the removal of the organism or part from the
stimulus.
Effects of drug on Behaviour
The human brain is the most complex organ in the body. This three-pound mass of gray and white
matter sits at the center of all human activity - you need it to drive a car, to enjoy a meal, to breathe,
to create an artistic masterpiece, and to enjoy everyday activities. In brief, the brain regulates your
basic body functions; enables you to interpret and respond to everything you experience; and
shapes your thoughts, emotions, and behavior.
The brain is made up of many parts that all work together as a team. Different parts of the brain are
responsible for coordinating and performing specific functions. Drugs can alter important brain
areas that are necessary for life-sustaining functions and can drive the compulsive drug abuse that
marks addiction. Brain areas affected by drug abuse 
The brain stem controls basic functions
sleeping.

The limbic system contains the brain's reward circuit - it links together a number of brain
structures that control and regulate our ability to feel pleasure. Feeling pleasure motivates us
to repeat behaviors such as eating - actions that are critical to our existence. The limbic
system is activated when we perform these activities - and also by drugs of abuse. In
addition, the limbic system is responsible for our perception of other emotions, both
positive and negative, which explains the mood-altering properties of many drugs.
critical to life, such as heart rate, breathing, and
The cerebral cortex is divided into areas that control specific functions. Different areas process
information from our senses, enabling us to see, feel, hear, and taste. The front part of the cortex,
the frontal cortex or forebrain, is the thinking center of the brain; it powers our ability to think,
plan, solve problems, and make decisions.
Here are summaries of the effect of selected drugs on the behaviour
Heroin
Heroin is a highly addictive opiate (like morphine). Brain cells can become dependent (highly
addictive) on this drug to the extent that users need it in order to function in their daily routine.
While heroin use starts out with a rush of pleasure, it leaves the use in a fog for many hours
afterwards. Users soon find that their sole purpose in life is to have more of the drug that their body
has become dependant on.
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Marijuana
The parts of the brain that control emotions, memory, and judgment are affected by
marijuana. Smoking it can not only weaken short-term memory, but can block information from
making it into long term memory. It has also been shown to weaken problem solving ability.
Alcohol
Alcohol is no safer than drugs. Alcohol impairs judgment and leads to memory lapses. It can lead to
blackouts. It distorts vision, shortens coordination, and in addition to the brain can damage every
other organ in the body.
Cocaine
Cocaine, both in powder form and as crack, is an extremely addictive stimulant. An addict usually
loses interest in many areas of life, including school, sports, family, and friends. Use of cocaine can
lead to feelings of paranoia and anxiety. Although often used to enhance sex drive, physical effect
of cocaine on the receptors in the brain reduce the ability to feel pleasure (which in turn causes the
dependency on the drug).
Inhalants
Inhalants, such as glue, gasoline, hair spray, and paint thinner, are sniffed. The effect on the brain is
almost immediate. And while some vapors leave the body quickly, others will remain for a long
time. The fatty tissues protecting the nerve cells in the brain are destroyed by inhalant vapors. This
slows down or even stops neural transmissions. Effects of inhalants include diminished ability to
learn, remember, and solve problems.
LSD
While some people use LSD for the sense of enhanced and vivid sensory experience, it can cause
paranoia, confusion, anxiety, and panic attacks. Like Ecstasy, the user often blurs reality and
fantasy, and has a distorted view of time and distance.
Steroids
Anabolic steroids are used to improve athletic performance and gain muscle bulk. Unfortunately,
steroids cause moodiness and can permanently impair learning and memory abilities.
Tobacco
Tobacco is a dangerous drug, putting nicotine into your body. Nicotine affects the brain quickly,
like other inhalants, producing feelings of pleasure, like cocaine, and is highly addictive, like
heroin.
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Methamphetamine
Known on the street as meth, speed, chalk, ice, crystal, and glass, methamphetamine is an addictive
stimulant that strongly activates certain systems in the brain.
Ritalin
This drug is often prescribed to treat attention deficit disorder. It is becoming an illicit street drug as
well. Drug users looking for a high will crush Ritalin into a powder and snort it like cocaine, or
inject it like heroin. It then has a much more powerful effect on the body. It causes severe
headaches, anxiety, paranoia, and delusions.
References:
1. Scheider, A.M. & Tatshis, B.(1998), Physiological Psychology(3 rd ed), Random
House, N.Y.
2. Leukal ,F.(2000), Introduction of Physiological Psychology(3rd ed), CBS Publishers,
New Delhi.
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