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Clicker Question _________is(are) the generation of unregulated electrical discharges from scar tissue in the gray matter of the brain, which causes the muscles in the body to contract. A) Polyneuritis (beriberi) B) The voltaic piles C) Galvanism D) Pellagra E) Epilepsy Pale Blue Dot Where are we? Last time I discussed… the evidence that led us to know that the nervous signal is electrical. biomechanical and bioelectrical devices produced by bioengineers that interface with the nervous system. This time I will discuss… the structure of neurons. the blood-brain barrier. how neurons generate the electrical message known as an action potential. multiple sclerosis (MS). synapses and excitatory and inhibitory postsynaptic potentials. botulism and Botox. Nerves Were Observed Under the Microscope By Antony van Leeuwenhoek in 1675 Nerves are Fibrous, Not a Cavity through which the Animal Spirits Flow “I…observed, that after those Nerves had been but a little while cut off from the eye, the filaments, of which they are made up, did shrink up….And upon this shrinking up, a little pit comes to appear…and ‘tis this pit in all probability, that Galen took for a cavity.” Stimulated Nerves Pass an Electrical Current Emil Du BoisReymond (1848), a student of Johannes Muller, provided evidence that the nervous principle is electrical by showing that stimulated nerves pass an electrical current along their length. Nerves are Made of Cells Theodor Schwann (1830s), a cofounder of the cell theory, who was also working with Johannes Muller, discovered that nucleus-containing cells, now known as Schwann cells, were a component of nerves. Schwann Cells Rudolf Virchow (1854), another of Johannes Muller’s students, discovered a fatty substance in the brain that he called myelin. Myelin is formed by the Schwann cells. The Structure of Neurons Otto Deiters (1865) found that nerves were also composed of another cell type, now known as neurons. The neurons have two different kinds of branching processes attached to the cell body: one which was tree-like, which he called "protoplasmic extensions", and another which was more like a long fiber, which he called "axis cylinder". Wilhelm His (1889) called the tree-like extensions, dendrites; Rudolph von Kölliker (1896) called the long projections axons and the cell itself was named the neuron by Heinrich Wilhelm von Waldeyer (1891). The Dendrites, Axon and Cell Body of a Myelinated Neuron The Brain is Composed of a Giant Network of Neurons Joseph von Gerlach (1880) proposed that the recently discovered nerve impulses studied by Emil du BoisReymond propagated from cell to cell across the axons and dendrites, and that the brain was formed by giant nets made out of a large number of interconnected filaments. The Brain is Composed of One Large Cell Camillo Golgi developed a silver stain that allowed the visualization of the internal reticular apparatus, now known as the Golgi body. After staining the brain, it seemed to Golgi, that all the cells fused to form a single cell so that the brain consisted of a continuous mass of tissue that shared a single cytoplasm. Disagreement on the Neural Structure of the Brain Using Golgi’s silver stain, Santiago Ramón y Cajal was able to see that the brain was not a single cell, but composed of individual neurons. Ramón y Cajal, with all due respect, disagreed with Golgi’s conclusion. Both Ramón y Cajal and Golgi won the Nobel Prize in 1906 despite their opposite views of the brain. Golgi got the prize for developing the techniques used to visualize the nervous system and Ramón y Cajal got the prize for describing the correct structure of the nervous system. The Brain is Composed of Individual Cells (Neurons) Ramón y Cajal concluded that neurons are discrete and autonomous cells that can interact. the neuron is the basic unit of the nervous system. there are gaps, now called synapses, that separate neurons. Information is transmitted in one direction from dendrites to the axon. Ramón y Cajal Traced the Networks of Neurons Over Small and Large Distances Ramón y Cajal Traced the Networks of Neurons Over Small and Large Distances Books by Santiago Ramón y Cajal Blood Brain Barrier Paul Ehrlich (1870s) injected various aniline dyes, produced by the new German dye industry, into the blood stream of animals and found that the dye stained everything but the brain. His student, Edwin Goldmann (1913) injected the aniline dyes into the brain fluid and found that the brain stained, but not the rest of the body. Lina Stern (1921) proposed that there was a blood-brain barrier that separated the brain from the rest of the body. Blood Brain Barrier Unlike the capillaries in the rest of the body that are “leaky”, the capillaries in the brain are tight because the membranes of the epithelial cells that make up the capillaries in the brain are tightly appressed to each other. Because of this, any chemical that leaves the blood stream and enters the brain must either be nonpolar and small enough to pass through the lipid bilayer or must have a specific transport protein to let it enter the intercellular milieu of the brain. The blood brain barrier protects the brain from viruses and toxins, but also makes it a challenge to deliver some drugs to the brain. Cell Types in the Brain The blood-brain barrier is composed of glial cells, called astrocytes, which help prevent many substances in the blood from entering the brain. Oligodendrocytes in the central nervous system (CNS), like the Schwann cells in the peripheral nervous system (PNS) are glial cells that surround the axons and make up the myelin sheath. The glial cells, which mean “glue cells” have multiple functions, including structurally supporting neurons and regulating the biochemical balance of the brain. They were discovered in 1856 by Rudolf Virchow. The dendrites and cell bodies of the neurons make up the gray matter of the brain and the axons make up the white matter. The Cell Types in the Brain Electrical Transmission Along Neurons The Plasma Membrane of Neurons The Plasma Membrane Contains Receptor Proteins and Transport Proteins, Including Ion Channels, and Ion Pumps Driven by the Energy of ATP Ion channels act as enzymes that reduce the activation energy or thermal energy that would be necessary to move a charged ion through a hydrophobic lipid bilayer. It Would Take a Lot of Heat to Move a Charged Ion Through the Lipid Bilayer. Because of Channels, Ions Can Move Through Aqueous Channels at Body Temperature The Influence of Ion Channels on the Movement of Ions Across a Membrane Hot Temperature→ Body Temperature→ Without the channel, the ions do not have enough energy at body temperature to pass through the plasma membrane. An Unequal Distribution of Ions on the Two Sides of a Membrane Leads to a Voltage Across the Membrane Known as the Membrane Potential Electrical Hyperpolarization of the Membrane When the inside concentration of a positive ion is greater than the outside concentration, the ion will tend to diffuse out of the cell using its thermal energy. The electrical potential inside the cell will become more negative and the membrane will be hyperpolarized. At some point, the membrane potential will become so negative that the outgoing positive ions will be attracted back into the cell and the ions will be at equilibrium at the hyperpolarized electrical potential. That is, the concentration difference driving the ions out of the cell will be equivalent to the voltage driving the ions back into the cell. Generation of an Electrical Potential Across the Membrane Initial Final (At Equilibrium) Assume inside of cell (1) and outside of cell is (2) and membrane is only permeable to the positive ion (K+) as a result of the ion channels present. At equilibrium, membrane is electrically hyperpolarized. Hyperpolarized and Depolarized Membranes • The electrical potential outside the cell is considered to be 0 volts by definition. • When the electrical potential inside the cell is more negative than 0 volts, the membrane is said to be hyperpolarized. • When the electrical potential inside the cell is less negative than the hyperpolarized potential, the membrane is said to be depolarized. Electrical Depolarization of the Membrane When the outside concentration of a positive ion is greater than the inside concentration, the ion will tend to diffuse into the cell using its thermal energy. If the membrane is already electrically hyperpolarized, the electrical potential inside the cell will become less negative and the membrane will be depolarized. At some point, the membrane potential will not be negative enough to attract any more positive ions into the cell and the ions will be at equilibrium at the depolarized electrical potential. That is, the concentration difference driving the ions into the cell is equivalent to the depolarized voltage driving the ions out of the cell. Generation of an Electrical Potential Across the Membrane Initial Final (At Equilibrium) High [NaCl] High [NaCl] Low [NaCl] Low [NaCl] Na+ Na+ Assume outside of cell (1) and inside of cell is (2) and membrane is only permeable to the positive ion (Na+) as a result of the ion channels present. At equilibrium, membrane is electrically depolarized. Walther Nernst Derived an Equation that Predicts the Equilibrium Potential Nernst Equation Equilibrium Potential = (kT/ze) ln ([ion]out/[ion]in) k = Boltzmann’s constant (1.38 x 10-23 J/K) T = Absolute Temperature (in K) = 310 K for humans e = elementary charge (1.6 x 10-19 C/charge) z = valence of ion (+1 for K+ and Na+) (kT/ze) ln ([ion]out/[ion]in) is the voltage equivalent of the concentration difference 1 Volt = 1 J/C = 1 Joule/Coulomb ln 10 = 2.3 The Nernst Equation (kT/ze) is always positive and equal for both K+ and Na+ ln ([ion]out/[ion]in) is positive when the outside concentration is greater than the inside concentration of an ion. ln ([ion]out/[ion]in) is negative when the outside concentration is less than the inside concentration of an ion. ln ([ion]out/[ion]in) is zero when the outside concentration is equal to the inside concentration of an ion (= death). Natural Logs Are Easy Ln 1000 = 6.9 Ln 100 = 4.6 Ln 10 = 2.3 Ln 1 = 0 Ln 0.1 = -2.3 Ln 0.01 = -4.6 Ln 0.001 = -6.9 Because the K+ concentration is greater inside the cell than outside the cell, K+ moving out of the cell tends to hyperpolarize the membrane. The Na+ concentration is greater outside the cell than inside the cell, but since the membrane at rest is relatively impermeable to Na+, Na+ has little effect on the electrical potential of the membrane at rest. Consequently, the resting membrane potential is given by the equilibrium potential for K+. Resting Potential Concentrations (in mol/m3) and Equilibrium Potentials (in V) of Cations Outside Inside Equilibrium Potential K+ 20 400 Na+ 440 50 -0.08 V +0.06V Measuring Membrane Potentials In Neurons With Microelectrodes Edgar Adrian (1928) placed small glass electrodes into many kinds of neurons and measured the single cell electrical variation that contributed to the whole nerve electrical changes that had been measured by Emil Du Bois-Reymond. The Action Potential: A Variation in Electrical Potential The Nervous Signal is like the Morse Code “If these records give a true measure of the activity in the sensory nerve fibres it is clear that they transmit their messages to the central nervous system in a very simple way. The message consists merely of a series of brief impulses….In any one fibre the waves are all of the same form….In fact, the sensory messages are scarcely more complex than a succession of dots in the __ __ . . . . . . . Morse Code.” ADRIAN'S LAWS Neurons communicate with each other by sending a short episode of electrical pulses, known as action potentials, along their fibers. A stimulus either induces an action potential in a neuron or it does not. It is an all-or-none response. The pulses do not vary in amplitude but vary in the frequency of the pulses. The frequency can be as high as 1000 impulses per second. Resting State Initiation of an Action Potential A stimulus causes Na+ channels to open and the influx of Na+ causes the membrane potential to depolarize (become less negative) beyond a threshold. Action Potential: Positive Feedback The membrane depolarization activates additional Na+ channels, whose conductance is voltagedependent. This causes a lot more Na+ to enter the cell and the membrane potential depolarizes further (and even becomes positive). Action Potential: Negative Feedback The Na+ channels do not remain open forever, but become inactivated. This causes the membrane to become repolarized (hyperpolarized again). Action Potential: K+ ions Once the membrane potential is depolarized by the Na+, the membrane potential is no longer negative enough to hold in the high concentration of K+ ions and the K+ ions begin to move out of the cell through the K+ channels. This enhanced K+ efflux, combined with the inactivation of the Na+ channels results in a return to the resting membrane potential and the action potential is over. Voltage Clamp Experiments The activation and inactivation of the Na+ channel was studied by Alan Hodgkin and Andrew Fielding Huxley using a voltage clamp. The properties of the channel were determined by holding the axon membrane at a depolarized potential (V). When the membrane is held at a depolarizing potential, the Na+ channel is activated and a current (I) carried by Na+ passes. The current is proportional to the membrane conductance (G). After a millisecond or so, the current stops, indicating that the channel becomes inactivated. Voltage Clamp Experiments Ohm’s Law V = IR R = V/I G = I/V Equivalent Circuit of Axon Membrane Membrane and channel conductance can be determined using Ohm’s Law. Equilibrium potentials act as batteries. Channels act as variable resistors. Lipid bilayer acts as insulator in a capacitor. Neurons are really miniature electrical devices!!!!! The Neuron Acts as if it is Composed of Electronic Parts http://artisresistors.co.uk/gallery.html Some Evidence for the Ionic Theory of Action Potentials An action potential can not be generated unless there are Na+ in the external medium. Radioactive Na+ are taken up by the neuron during an action potential. Pharmacological agents that inhibit Na+ channels, like tetrodotoxin, which is isolated from the puffer fish, prevent the action potential. Refractory Period and Unidirectionality The Na+ channel remains inactivated for slightly longer than it takes to bring the membrane back to the resting potential. Thus, the section of membrane that just finished an action potential is not able to produce another one until the Na+ channel is no longer inactivated. The period of time necessary for the Na+ channel to become sensitive to a stimulus is known as the refractory period. The refractory period makes it possible for an action potential to move down a neuron in only one direction. Due to the refractory period, the action potential moves along the axon unidirectionally. Nodes of Ranvier The membranes of the glial cells that form the myelin sheath around the axon are almost purely lipid. Since ions cannot pass through lipids, the myelin sheath acts as a insulator around the conducting axon. Each Schwann cell is separated from the next by a node of Ranvier, where the sodium and potassium channels are. The combination of the glial cells and the nodes of Ranvier make an electrical capacitor that causes the voltage to “jump” from node to node. Myelin Sheath Results in a High Conduction Velocity Action potentials move down the axon jumping from node to node at a rate of 150 m/s (= 330 mph). Without the myelin sheath, the action potential would travel about 5 m/s. Multiple Sclerosis Multiple sclerosis is an autoimmune disease in which the white blood cells of the body consider the oligodendrocytes that form the myelin sheath around the neurons of the central nervous system to be foreign invaders and destroy them. The degeneration of the myelin sheath results in a slower conduction velocity of action potentials and a loss of control of neural processes. What Happens to the Electrical Impulse When it Gets to the End of the Cell? How Can an Electrical Signal Stimulate Some Cells and Inhibit Others? Stimulatory and Inhibitory Actions of Neurons When one provokes a a reflex movement, a contraction of one muscle is accompanied by a relaxation of an opposing muscle. Since all muscles are stimulated by a depolarizing voltage shock and all action potentials involve the transmission of a membrane depolarization, Charles Sherrington suggested that action potentials must be capable of doing at least two different things at synapses, one stimulatory and one inhibitory. Excitatory and Inhibitory Synapses While working on reflexes, Sherrington discovered that the there are two types of synapses: excitatory and inhibitory. The same concepts of excitation and inhibition appeared again in the sympathetic and the parasympathetic nervous systems. Sympathetic and Parasympathetic Nervous System Since the sympathetic and the parasympathetic nerve systems have opposite effects on cardiac muscle, there must be two different actions at their synapses: one excitatory, another one inhibitory. No one could figure out how an electrical message, in the form of an action potential going to the same postsynaptic element would achieve totally opposite effects, so some turned to the idea that excitatory and inhibitory chemical messengers may be involved. Chemical Synapses? Thomas Elliot (1904) could mimic the excitatory effects of the sympathetic nervous system on cardiac muscle with an extract of the adrenal medulla known as adrenaline. Henry Dale (1920s) could mimic the inhibitory effects of the parasympathetic nervous system on cardiac muscle with an extract from ergot of rye, known as acetylcholine. Dale coined the terms "adrenergic" and "cholinergic" synapses to describe the chemicals that may couple the neural stimulus to the cardiac muscular response. Henry Dale By 1936, Henry Dale concluded that, "According to this relatively new evidence, a chemical mechanism of transmission is concerned, not only with the effects of autonomic nerves, but with the whole of the efferent activities of the peripheral nervous system, whether voluntary or involuntary in function." Occam’s Razor Sliced a Little Too Close Electrophysiologists did not want to believe in chemical signals. They invoked Occam’s Razor, claiming that there is no need for two kinds of signals. In general, as scientists, we are reductionists and try to simplify things as much as possible. But biological systems are never as simple as reductionists postulate. Graded Potential Responses John Eccles (1952) began to insert microelectrodes into the cell bodies of postsynaptic neurons of the CNS. After stimulating either excitatory or inhibitory presynaptic nerves, he discovered that there were two kinds of graded potential responses in the post-synaptic cell. The Excitatory Graded Potential The excitatory response depolarized the post-synaptic nerve cell, bringing the membrane potential closer to the threshold. This would increase the probability of activating voltage-dependent Na+ channels and initiating an action potential in the post-synaptic cell. The Inhibitory Graded Potential The inhibitory response hyperpolarized the postsynaptic nerve cell, bringing the membrane potential further from the threshold. This would decrease the probability of activating voltage-dependent Na+ channels and initiating an action potential in the post-synaptic cell. The Excitatory (EPSP) Graded Potential Results from the Activation of Voltage-Independent Na+ Channels The Inhibitory (IPSP) Graded Potential Results from the Activation of Voltage-Independent K+ Channels or Voltage-Independent Cl- Channels Integration by the Post-Synaptic Neuron The sum of all the excitatory (+) post synaptic potentials (EPSP) and the inhibitory (-) post synaptic potentials (IPSP) determine the probability of initiating an action potential in the postsynaptic cell. Integration by the Post-Synaptic Neuron: The Basis of Decision Making? When a large number of excitatory postsynaptic potentials (EPSP) and a small number of inhibitory post-synaptic potentials (IPSP) are evoked, the post-synaptic membrane is depolarized and the post synaptic neuron becomes likely to initiate an action potential. If a small number of excitatory post-synaptic potentials (EPSP) and a large number of inhibitory post-synaptic potentials (IPSP) are evoked, the post-synaptic membrane becomes hyperpolarized and the post synaptic neuron is unlikely to initiate an action potential. The Post-Synaptic Cell is an Analog to Digital Converter The Post-Synaptic Cell is also an Integrator In the Post-Synaptic Cell, the Majority Rules Integration Can Take Place Over Time (from a single Pre-synaptic Neuron) or Over Space (from Many Pre-synaptic Neurons) Excitatory and Inhibitory Neurotransmitters Whether a pre-synaptic neuron is excitatory or inhibitory depends on the neurotransmitter that is released. Excitatory neurotransmitters include: acetylcholine (neuromuscular junction of skeletal muscle) noradrenaline glutamate (an amino acid) Inhibitory neurotransmitters include: acetylcholine (neuromuscular junction of cardiac muscle) glycine (an amino acid) GABA How does an action potential trigger neurotransmitter release in a neuromuscular junction? The membrane depolarization at the pre-synaptic membrane due to the action potential opens calcium channels. The calcium entering the cell acts as a second messenger to trigger the secretion of acetylcholine by exocytosis into the neuromuscular synapse. Stimulus-Response in Neurons Stimulus: Action potential (membrane depolarization) Receptor: Voltagedependent Ca2+ channels Second Messenger: Ca2+ Response: Secretion of neurotransmitters Neuromuscular Junction of Skeletal Muscle Acetylcholine is the neurotransmitter released in the neuromuscular junction. The acetylcholine receptor is a Na+ channel. The activation of which causes a depolarization of the muscle cell membrane, which causes voltage-dependent Ca2+ channels to open, which causes the muscle to contract. Food Poisoning: Botulism (Clostridium botulinum) Botulinum Toxin Causes Paralysis by Blocking Acetylcholine Release Every Cloud Has a Silver Lining Weight for weight, botulinum toxin is the most toxic of toxins. However, it can be used for cosmetic reasons—where it is sold under the name botox. Botox: Botulinum Toxin Injections Prevent Contraction of the Muscles that Result in Frowning Cosmetic Botox Injection Cosmetic Botox Injections Botox Scam: Priscilla Presley Got Low Grade Silicone Instead of a “Superior Grade of Botox” The Chemical Basis of the Individual’s Mind As I will discuss in the next lecture, there are many different neurotransmitters, especially in the brain, that can induce either excitation or inhibition of the post-synaptic membrane. Due to differential transcription and alternative splicing, there is a variety of receptors for each neurotransmitter in different post-synaptic neurons. Moreover, allelic differences between individuals lead to genetically-determined differences in receptors. The near-limitless combinations allow for near infinite individual variations in the chemical basis of mind. The Mind-Body Problem: Original Thoughts Is the mind an emergent property of hundreds of billions of material brain cells? If so, One day it will be possible to electrically stimulate the brain with a number of electrodes in such a way as to create an original thought. One day it will be possible to introduce a combination of chemicals into the brain and create an original thought. The Mind-Body Problem: Original Thoughts Does the mind have its own energy that is capable of influencing the physicochemical processes in the brain and induce action potentials? According to Wilder Penfield (1975) “…there is no good evidence . . . that the brain alone can carry out the work that the mind does. . . . I believe that one should not pretend to draw a final scientific conclusion, in man's study of man, until the nature of the energy responsible for mind action is discovered, as in my own opinion, it will be." Free Will “Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom.” Viktor Frankl Free Will “The very serious and difficult question arises of whether…free will is compatible with our scientific knowledge, which plainly says that the concept of a breach in causal continuity is not acceptable. From the point of view of science, the reality of free will cannot be conceded. On the other hand, as human beings, we depend on the belief that…our actions are preceded by deliberation and choice….” Hans Mohr Free Will “All I have to say is that free will is a fact of experience….Free will is often denied on the grounds that you can’t explain it, that it involved happenings inexplicable by present-day physics and physiology. To that I reply that our inability may stem from the fact that physics and physiology are still not adequately developed.…” John Eccles Science and Free Will I believe that we can exercise and develop our neurons to transform food energy into “free will energy”, which acts locally (100 nm range) and at levels of about 10-20 - 10-19 J. Perhaps “free will energy” could modify a calcium channel in the presynaptic neuron or modify a receptor in the postsynaptic neuron and cause us to do or not do something (e.g. something that takes courage). Zorba the Greek It may be that we can choose to convert our food into fat, work, or spirit. Profiles in Courage Award In whatever arena of life one may meet the challenge of courage… each…must decide for himself the course he will follow…. —John F. Kennedy Profiles in Courage A Profile in Courage Plant and animal cell biologist Werner Franke exposed illegal East German steroid research and the illegal doping of athletes. Another Profile in Courage Dr. Ignacio Chapela is courageous in “disentangling reality from corporate advertising” in his ecological studies at UC Berkeley. www.nature.com