Download Neuroscience - Exam 1

Neuroscience - Part 1
by Batmanuel
 The Structure of Neurons and Glia
○ Membrane channels are either voltage gated or ligand gated
○ Classification of neurons
 Unipolar (rare in mammals), Bipolar, Multipolar
 Pseudounipolar - single process bifurcates close to soma into a dendrite-like peripheral process (distal
axon) and an axon-like central process (central axon)
○ Neurons are very specialized but can’t reproduce
○ Anatomy of Neuron
 Cell Body
 Renews 1/3 of its protein a day
 Nissl Bodies - ribosomes clump up, unique to neurons
 Three classes of proteins - cytosolic, mitochondrial/nuclear, membranous
 Filaments
 Microtubules - transport of membrane proteins and organelles throughout cell
 Neurofilaments (intermediate filaments) - primarily structural, usually in parallel bundles
 Microfilaments - similar to thin filaments in skeletal muscle (primarily structural)
 Dendritic spine - outpocketing of the dendritic membrane which receives synaptic contacts
 Axon - only one per neuron, but can branch off
 Diameter is correlated with conduction velocity
 Axoplasmic Transport - 98% of protein in axons originates in cell body
○ Microtubule dependent
○ Anterograde - to axon terminal
 Slow - 1-4 mm a day, transports cytoskeletal proteins and cytosolic enzymes
 Fast - 50-400 mm a day, transports membrane associated proteins, organelles and
neurotransmitters
 Uses kinesin
○ Retrograde - from axon terminal
 200 mm a day, transports worn out membrane components for recycling
 Uses dynein
 Axonal Ensheathment
○ All axons are ensheathed by the cytoplasmic processes of glial cells, just vary in amount
○ Myelinated - multilayered covering of myelin for large diameter axons
○ Unmyelinated - single layer covering for small diameter axons
○ CNS - one oligodendrocyte for several axons
○ PNS - one Schwann cell for multiple axons
 Synapse
 Axosomatic - when synapse is with cell body
 Electrical Synapse - connected by gap junctions and utilizes voltage-gated iontophores
 Chemical Synapse - uses vesicle bound neurotransmitters
○ Have synaptic boutons and synaptic densities (aggregations of electron dense materials)
 Presynaptic density - conical protrusions of varying thickness on the cytoplasmic side of the
presynaptic membrane which help dock the synaptic vesicles to membrane for exocytosis
 Postsynaptic density - thicker, more homogenous plaque
 Types
○ Asymmetric - postsynaptic density thicker than presynaptic density is often excitatory
○ Symmetric - often inihibitory
○ Types of Synaptic Vessicles
 Round Clear - generally excitatory and found in asymmetrical synapses
 Flattened Clear - generally inhibitory and found in symmetrical synapses (GABA)
 Dense Core - thought to be associated with catecholamines (epinephrine and norepinephrine)
 Nerves and Tracts
 Nerve - collection of axons outside brain and spinal cord
 Tract - collection of axons inside brain and spinal cord
 Sheaths
○ Endoneurium - single axon or nerve fiber
○ Perineurium - small bundles of axons (fasicles)
○ Epineurium - around entire nerve and fasicles
○ Blood/Brain Barrier
 Components
 Capillary endothelial cells with tight junctions
 Mesenchymal-like cells called pericytes which surround the endothelial cells
 basement membrane of endothelial cells
 foot-like processes of astroglial cells which connect to basement membrane of endothelial cells
 Transport across the barrier usually involves active transport
 Neuroglia
 CNS
○ All neuronal surfaces except synapses covered by them
○ Outnumber 50:1 but make up only 50% of volume
○ Can reproduce and thus are the source of CNS tumors
○ Types
 Oligodendrocytes - myelin forming cells
 Astocytes - star shaped cells with radially oriented processes
○ Fibrous astrocytes - associated white matter
○ Protoplasmic astrocytes - associated with neuronal cell bodies (grey matter)
 Found in close association with blood vessels
○ Provide mechanism for exchange of nutrients and waste between neurons and blood
○ Proliferate at site of neuronal damage
 Microglia - phagocytes of the CNS, part of the mononuclear phagocytes system
○ Smallest gial cells, have numerous highly branched processes
 PNS
○ Schwann Cells - one per customer
○ Satellite Cells - surround neuron cell bodies and don’t have much cytoplasm
 Function not exactly clear, could have nutritive support
 Regional Anatomy of the CNS and Brain Vasculature
○ THIS LECTURE NEEDS WORK
○ Objectives
 Know Landmarks
 Spinal cord, anterior and dorsal cell columns
dorsal, lateral, anterior funiculi
 Brainstem, medulla oblongata, pons, midbrain, cerebellum, cortex and deep nuclei
 Cranial nerves, lobes and important gyri
 Thalamus, hypothalamus, caudate nucleus, putamen, globus pallidus, internal capsule, corpus callosum
 Ventricular system
 Describe
 Composition of cranial vault
 Dura mater and dural reflections, arachnoid membrane, pia mater
 Distribution of the major branches of the internal carotid artery and the vertebral aterty
 Major patterns of venous drainage
 The formation, circulation and resorption of cerebrospinal fluid
○ Meninges - coverings of the nervous system
 Is innervated
 Dura mater
 Arachnoid mater
 Pia mater - soft, gentle supporting tissue
 Meningitis - inflammation, will cause very bad headache, backache, stiffness
○ Encephalon - (within the head)
 Developmental terms that continue through to maturity
 Prosencephalon - (ahead of encephalon) Forebrain, which is made of cerebrum, thalamus and
hypothalamus
 Mesencephalon - midbrain, includes brainstem
 Rhombencephalon - hindbrain, includes brainstem (pons and medulla) and cerebellum
 Encephalitis - inflammation of the brain
○ Nerve Fibers
 Functional Classifications
 Projection Fibers - connect different major levels of the nervous system (ie spinal cord and
forebrain, cerebrum and spinal cord)
○ Often decussate - means to cross the midline
 Don’t all decussate at the same place
 Often influence the contralateral side
 Association Fibers - Connect same level of nervous system (ie within cerebellum, within spinal
cord)
○ Connect different/similar functional areas together
○ Don’t decussate (stay on same side)
 Ex. Connect visual area with auditory to motor area
 Commissural Fibers - connect similar areas of the brain from hemisphere to hemisphere (through
corpus callosum)
○ Connect similar areas (sensory to sensory)
○ Decussate
○ Spinal Cord
 Beins at foramen magnum, ends at L1-L2
 Grey Matter Parts
 Anterior Horn - contains cell bodies of lower motor neurons (cell body in CNS, axon goes to PNS
and innervates)
 Dorsal Horn - receive info from primary sensory neurons of DRG (their cell bodies are in the
DRG or cranial nerve and the peripheral process picks up sensory info in the PNS. The central
process goes through the DRG and ends in CNS
 White Matter Parts
 Funiculi - columns of both
ascending and descending
projection fibers (posterior, lateral
and anterior)
 Most white matter in top levels of
spinal cord and least in the lower
levels (because it accumulates as
you go up)
 Differences of composition between
different levels of spinal cord
○ Cervical - larger anterior horn
because there are lots of motor
neurons controlling the arms here
 Lateral anterior funiculi relates to upper limb
 Medial anterior funiculi relates to axial musculature
○ Thoracic - loses lateral portion of the anterior funiculi (since no upper limb there)
○ Sacral - much less white matter
 Large anterior horn because lots of motor neurons controlling the legs

○ Cerebrum
 Brain is just a little heavier than neutral buoyancy (rests a little bit upon base of skull)
 Dura mater creates dural reflections that protrude into the cranial cavity making the falx cerebri and
tentorium cerebelli
 Falx cerebri - divides left and right cerebral hemispheres
○ Makes sure that the one side doesn’t smush the other when laying on side
 Tentorium cerebelli - divides cerebrum and cerebellum
○ Supports posterior half of the cerebrum so that it doesn’t push down on the cerebellum
○ Tentorial notch - opening in the tentorium cerebelli that allows the midbrain to pass
○ Divides cranium into superior and inferior regions (roughly)
○ Oculomotor nerve comes out of midbrain and midbrain would be pushed out with brain swelling
and thus pupils would be messed up
 Lateral Fissure - separates temporal lobe
 Central Sulcus - divides frontal and parietal lobes of brain
 Precentral sulcus - in frontal lobe, motor area
 Postcentral sulcus - in parietal lobe, sensory area
 Frontal lobe - often motor behavior, thoughts
 Parietal lobe - often perception
 Temporal - hearing, memory formation
 Insular - deep to the lateral fissure (buried behind things)
 Visceral activity controlled here
 Calcarine fissure  Limbic lobe - a functional lobe
 Around juncture of cerebral hemisphere and brainstem
 Includes cingulate gyrus
 Connects calculating non emotional areas of brain to the areas that express emotion and autonomic function
 Grey matter is not only on the outside of the cerebrum, it is also on the inside (called deep grey
matter)
 Ex. Thalamus and ganglia (Everything passes through thalamus (it is the gatekeeper))
 Corpus Callosum - contains commissural fibers
 Cerebellum also has cortex of grey matter and also deep grey matter
○ CSF
 Cranial subarachnoid space is continuous with spinal subarachnoid space
 CSF is kind of like lymphatic tissue because it is just extra fluid
 Capillaries often release more fluid than they let back in and so that extra fluid has to go somewhere
 Resorbed in
 Dural venous sinuses
 Can be resorbed anyplace that a nerve leaves the central portion of the nervous system and the bony
housing
 Membrane Excitability I - Passive Properties, Ionic Gradients, and resting potential
○ Objectives
 Understand the fluid-mosaic structure of the plasma membrane, and the concept that embedded ion channels and
pumps underlie many specialized membrane functions
 Understand the structure of ion channels and their classification as voltage-gated, ligand-gated, leak and gap
junction channels
 Be able to define current, voltage, resistance, capacitance, depolarization and hyperpolarization
 Be able to describe how differences in transmembrane ion concentration and voltage determine the driving force
on ions in solution
 Understand the special circumstances under which electrochemical equilibrium is achieved
 Be able to use the Nernst Equation to predict the equilibrium potential for ions distributed inside and outside of
cells
 Be able to use the Goldman Equation to explain the resting membrane potential in terms of ionic concentration
gradients and selective membrane permeabilities for K and Na
 Define the two major types of ion pumps and understand the structure and function of the Na/K ATPase
○ Ion Channels as Resistors
 Ion channels have an aqueous pore (.15 nm in diameter) filled with a salt solution
 Thus it acts like an electrical conductor with resistance since it impedes charge movement
1 I
○ G 
(G= conductance)
R V
○ resistance of the pore is related to the medium’s resistivity and the pore dimensions (length and area)
○ Cell Membrane as a Capacitor
 Capacitor - device that separates electric charge (insulator)
 Cell membranes act as capacitors by preventing the flow of charge from one side to the other
Q
 C
V
○ ie. the electric potential (V) across a capacitor is directly related to the stored charge (Q)
○ a conductor provides a pathway for the passage of charge over time
 When charges are separated from each other they create a voltage (a form of potential energy)
 1V = work required to move 1 coulomb through 1 meter against a force of 1 newton
○ The cell membrane can be thought of as an electrical circuit containing capacitors (lipids)
and resistors (ion channels) in parallel
○ Cells act as passive resistors since they respond passively if a voltage is added to them?
○ Types of Ion Channels
 Voltage-Sensitive (gated)
 Very selective for their named ions
 Voltage-gated Na+ and Ca2+
○ 4 domains, each containing 6 MSRs (membrane spanning regions), of a single alpha subunit
polypeptide
 the central pore is made of the 5&6 MSRs
 Voltage-gated K+
○ 4 individual subunits
 Voltage-gated K+ inward rectifier
○ Different because it opens in response to hyperpolarization
○ 4 subunits, each containing 2 MSRs (each flank the central pore, thus 1P/2TM)
 Voltage-Insensitive (ligand gated)
 Much less selective for ionic species, in general they are ‘valence’ selective
 Acetylcholine Receptor
○ 5 subunits, each containing 4 MSRs
 the central pore is lined by the M2 portion
 Gap Junction Channels
 Paired channels (connexons) that meet across membrane junctions
 Generally non-selective because of their large pore size
 Some are weakly gated by pH and/or Ca2+
 Leak Channels
 K+ selective pores
○ 4 MSRs and 2 pore domains (2P/4TM)
○ Resting Potential
 Resting potential is not an absolute value, it varies cell to cell and also from time to time
 It is not an equilibrium, it is a steady state
 Determined by the electrochemical gradient
 K+ leaks down its concentration gradient and the leak is opposed by the resulting membrane
potential
 Electrochemical gradient represented by Nernst Equation (at standard conditions)
X 2 (z=valence)
58
○ E x  log
X 1
z
 ie. a 58 mV change in V(1-2) for every 10 fold change in concentration
 It takes a very little amount of K+ separation to generate substantial membrane potentials
 Amount of ions needed to make gradient infintessimal compared to surrounding concentrations
 K+ is the main determinant of resting potential, but it is not the only determinant
 At high concentrations of extracellular K+ the Nernst Equation holds true
 At low concentrations of extracellular K+ then other ions play a role in determining resting potential
○ The effects of other ions are modeled by the Goldman Equation, which requires knowledge of
the permeabilities of each ion
 Assumes that each ion responds independently to their respective driving forces
○ Ion Pumps
 Types
 ATPase pumps
○ Na+/K+ pump - keeps K+ high inside and Na+ high outside
○ Ca2+ pump - keeps intracellular Ca2+ low
 Ion Exchange Pumps - carry one or more ions against their concentration gradient while taking
another ion down its gradient (ultimately dependent on ATPases since they are depended on
gradients)
○ Na/Ca - pumps Ca out, Cl/HCO3 - pumps Cl out, Na/H - pumps H out
 Na/K ATPase
 Properties
○ Requires Na, K and ATP
○ Oubain (a toxin) will block the pump’s function
 Process
○ 3 intracellular Na bind and pump gets phosphorylated by ATP
○ Causes conformational change that exposes the Na to extracellular fluid, Na then release and 2 K bind
○ Dephosphorylation then results in a reverse conformational change leading to intracellular K release
 Structure
○ 10 MSRs, just 1 peptide
○ Intracellular domain required for ATP binding and hydrolysis
 Voltage-gated Channels and Action Potentials
○ Objectives
 Define action potential nomenclature: resting potential, threshold, depolarizing phase, overshoot,
hyperpolarizing phase, after-hyperpolarization
 Describe general features common to voltage-gated Na, Ca and K channels and recognize the key structural
elements that give the channels their specific properties: voltage dependence, gating, ion selectivity and
inactivation
 Describe how ion flow through voltage-sensitive Na and K channels produces macroscopic membrane currents
which also show features of activation and inactivation and when combined with appropriate kinetic parameters
produces an action potential
 Explain the concepts of threshold and refractory period in terms of events at the level of single channels and
ions
 Define the concept of “length constant” and describe how this relates to current flow from one region of an axon
to adjacent membrane areas
 Describe how action potentials are conducted in myelinated and unmyelinated axons and explain how
demylinating disease affects conduction of action potentials
 Predict how effectively neurons exhibit spatial summation of non-propagated currents based on a knowledge of
the space constant
 Explain what is meant by the time constant of a neuron and describe how temporal summation transforms neural
signals from a frequency code to an amplitude code
○ All long distance transfer of information in the nervous system requires action potentials
 Exception - in some places in the retina and olfactory bulb, interconnections between nerve cells are so
short that info is transferred without APs
○ EPSP - Excitatory postsynaptic potential - a depolarization that may or may not lead to AP
○ Important voltage landmarks in an action potential
 ENa - Sodium equilibrium (+59 mV) - the equilibrium for sodium after the absence of all other factors
 Threshold
 Voltage change to overshoot determined by sodium conductance
 Overshoot - (+20 mV) - positive physiological extreme
 Voltage change after overshoot determined by potassium conductance
 After-hyperpolarization - (-78 mV) - negative physiological extreme
 EKa - Potassium equilibrium - (-87 mV) - the equilibrium for potassium in absence of all other factors
○ Action potentials require sodium ions in the extracellular fluid
 The overshoot of the AP is determined by sodium concentration in the extracellular fluid
○ Structure of Voltage Dependent Channels
 Protein Structure
 K Channel
○ 4 domains - 6 MShRs (they are helical)
○ non-helical structure that spans the membrane between S5 and S6 that forms pore loop
 Ca and Na Channel
○ Single peptide, Alpha subunit has 6 MShRs (they are helical)
○ non-helical structure that spans the membrane between S5 and S6 that forms pore loop
 Voltage Sensing Region
 S4 on intracellular side and influences the conformation of the gating mechanism
 Is positively charged so that after depolarization (more +), it responds
 Channel Pore and Selective Permeability
 Hydrophilic amino acids form the wall of the channel found in the non-helical S5-S6 region
 Selective permeability depends on diameter of the hydrated ion, amount of energy needed to strip
off the water molecules
 Gating Mechanism
 Opens to let ion through, but is kind of slow to close
 Inactivation Region (not on all channels)
 Is positively charged and as positive charge enters the cell it closes the pore
 As resting potential is reached again it causes the postitively charged inactivation region to go back
to its normal place
 Anchor Protein - made of neurofilaments (actin) and anchors channel to specific locations
○ Subunits of Voltage Dependent Channels
 Sodium and Calcium - Large alpha subunit with 4 domains surrounding the ion pore
 Sodium - Beta subunits are smaller and are regulatory
 Calcium just have more
○ Local Anesthetics
 Physically block Na channel pore
 Long acting - more lipophilic molecules can enter fast or slow???? And thus stay there a long or
short time???
 Short acting - less lipophilic molecules can enter fast or slow???? And thus stay there a long or
short time???
○ Channel Currents
 Inward Current - positive ion into cell (downward deflection)
 Outward Current - positive ion out of cell (upward deflection)
 The probability that a channel will open increases with depolarization of the membrane and is a
sigmoid relationship
 Experiment
 Give a uniform voltage change to a membrane
and see what happens
○ View Na Channels only (use tetraethyl
ammonium to block K channels)
 Channels immediately open then close
 Do not reopen even though voltage
change is still present (they
inactivate)
○ View K Channels only (use
tetrodotoxin to block Na channels)
 Channels open in a delayed manner
 Stay open until voltage change is
removed (do not inactivate)
○ Both sets of channels together (see right)
 View Conductances over time (see right)
○ Sodium conductance is fast and
potassium conductance is slower
 Channelopathy - Paramyotonia Congenita
 A defect in the Na channel where it can’t inactivate it in time so you get longer APs and things get
messed up.
 Goats get it and when they get excited they fall down
 Nerve Crush Injury
 In nerve crush injury Na V1.3 channels are upregulated and they are hypersensitive
○ They cause the pain of carpal tunnel syndrome, sciatica etc.
 Threshold
 For each small depolarization there is:
○ Positive feedback - increased positive charge increases the probability that more Na channels
will open to let more + in
○ Negative feedback - increased positive charge increases the probability that more K channels
will open to let more + out
 At threshold, each Na that enters and contributes one + charge is counterbalanced by the loss of one
K+ ion
 Refractory Period
 Absolute refractory period - when no amount of depolarization can cause another AP
○ Mainly due to the inactivation of the Na channels
 Relative refractory period - when a second AP is possible, but a larger stimulus must occur to get
it there
○ Mainly due to the K channels overshooting the resting potential
○ Length Constant - point at which you start a current to where it diminishes to 63% of its original
 Current flow in the axon is affected by two things
 Internal resistance of the cytoplasm
○ Thus thicker axons have longer length constants
 a given amount of current will flow further in a thick axon than in a small axon
 Its dissipation through passive leak channels across the membrane
○ Thus myelinated axons will have longer length constants
membrane Re sis tan ce axonDiameter
 lengthCons tan t 
axoplasmic Re sis tan ce
 Graded potentials produced by passive currents degrade over distance, thus a longer length constant
will get it to travel farther
 Action potentials don’t have to worry about this since they are self-renewing
○ The speed of APs is very much dependent on the length constant however
 Shorter length constant relates to slower transmission
○ Types of Peripheral Nerve Fibers
Class
Ia and Ib
II
III (A-delta)
IV (C fibers)
Axon Diameter
Myelin Thickness Conduction Speed
12-20
+++
70-120
5-14
++
25-70
2-7
+
10-30
.5-1
0
<3
○ Demyelinating Disease - Multiple Sclerosis
 Myelin leaves and the channels still stay in bunches at the nodes of ranvier
 This is bad because APs get lost or transmission slows between the bunches
 Eventually more channels get made to fill in between the bunches
○ Current Flow in Dendrites
 Current flow diminishes with distance in dendrites too and this factor greatly determines the
effectiveness of EPSPs or IPSPs.
 Synapses at positions nearer the cell body are more effective than more distal ones
 Synapses at thicker dendrites are also more effective
 Thus the geometry of a neuron’s dentrites is an important feature of its information processing
 Spatial Summation - process of combining currents from synapses at different locations in a neuron
○ Time Constant




How fast passive voltage change will occur across a membrane
Proportional to both the resistance and the capacitance of the membrane (T=RC)
Temporal Summation - EPSPs can add together if they arrive at a rate close to 1/T
Time Constant as a Smoother
 Since the presynaptic axon is transmitting a pulse of APs, the time constant reduces those jagged
pulses into a smooth signal, which effectively makes it like a filter
 Synaptic Transmission
○ Objectives




Be able to recognize the structural components of chemical and electrical synapses and identify their functions
Describe the sequence of events underlying transmission at a typical fast chemical synapse
Explain the quantal nature and Ca dependence of transmitter release from presynaptic nerve terminals
Be able to explain the basic molecular mechanisms though to be involved in neurotransmitter release at a fast
chemical synapse
 Summarize the activation and gating of postsynaptic nicotinic acetylcholine receptor channels
 Understand the different conductance mechanisms underlying excitatory versus inhibitory fast synaptic
transmission
 Be able to distinguish fast from slow chemical transmission and describe the relevant mechanisms
○ Neurotransmitters are released due to Ca
○ Electrical Synapses
 Made of transmembrane ion hemichannels called connexons
 6 subunits, non-selective
 Allow synchronous excitation or inhibition of coupled neurons
 Also allow metabolites through
○ Comparison
Distance between pre and
postsynaptic
Cytoplasmic continuity?
Ultrastructural components
Agent of transmission
Synaptic delay
Direction of transmission
Electrical
Chemical
3.5 nm
30-50 nm
Yes
Gap junction channels
(connexons)
Ionic current
Virtually absent
No
Presynaptic active zones and vesicles;
postsynaptic receptors
Chemical transmitter
Significant; at least .3 ms, usually 1-5
ms
Unidirectional
Usually bidirectional, can be
unidirectional
○ Chemical Synapses
 Steps
 AP depolarizes the presynaptic terminal and activates the Ca channels, causing an ↑ in terminal [Ca]
 ↑Ca triggers synaptic vesicles to fuse with presynaptic membrane and release neurotransmitter
(this generally occurs at the active zone)
 Neurotransmitter binds to receptor, which causes their ion channels to open
 Emptied vesicles are retrieved into an endosomal compartment and refilled with newly synthesized
neurotransmitter
 Excess neurotransmitter is removed either by enzymes that break it down or by reuptake
 Vesicles - General rule - Excitatory synapses have round vesicles, inhibitory synapses have
flattened vesicles
 Synaptic Function
 Size of muscle EPP (thus synaptic transmission and neurotransmitter release) is critically dependent
on the concentration of extracellular Ca
○ Layman’s terms - you need Ca to release neurotransmitter from vesicles
 Neurotransmitters are released from terminals in packets (quanta or vesicles)
○ MEPP - miniature endplate potentials occurred randomly under their experimental conditions
and were the release of one vesicle
○ Number of quanta released governed by m=np where n is number of quanta possible and p is the
probability that they will be released?? (the real equation is more complicated)
 Their resulting distribution was a binomial curve
○ Molecular Mechanisms of Transmitter Release
 SNARES
 V-SNARE (synaptobrevin) - found on the vesicle
 T-SNARE (syntaxin and SNAP-25) - found on the terminal plasma membrane
 These two snares form a complex and dock the vesicles at release sites
 Synaptotagmin - A vesicular protein that binds Ca and likely causes neurotransmitter release
○ EPP from Nicotinic ACh receptor channels
 Molecular Structure
 5 transmembrane subunits (with two alpha subunits)
○ one ACh molecule binds to N-terminal domain on each of the alpha subunits
 Ionotropic receptors - because they permit the transit of ions through a channel pore
 Physiology
 Gating
○ An ACh molecule must bind to both alpha subunits on the receptor and then it can open very
quickly (the binding and then opening is called activation, it doesn’t happened directly?)
 It stays open for a short period of time and then closes
 It can reopen, then close and repeat. During all of this the ACh stays bound
○ After a number of cycles the gate stays closed, the ACh dissociate and are cleaved by
acetylcholinesterase
 Permeation
○ The ACh channel is selective for monovalent cations and causes an inward current
○ Excitatory vs Inhibitory Synaptic Function
 Reversal Potential (Erev) - when there is no net current or net voltage change
 EPSPs and IPSPs
 EPSP - endplate potential that ↑ the likelihood that the postsynaptic cell will fire an AP
 IPSP - endplate potential that ↓ the likelihood that the postsynaptic cell will fire an AP
 Whether an input is excitatory or inhibitory depends on the ion selectivity of the postsynaptic cell’s
receptor and its Erev
○ Examples
 EPSPs for glutamate receptors
○ Glutamate receptors are selectively permeable to Na and K, whose E rev is about 0 mV (ENa = 60,
Ek = -100). So when the channels open, since the resting potential is -70, it will bring the cell
towards 0 mV and thus make an EPSP
○ If Erev > threshold then excitatory
 IPSPs for GABA receptors
○ GABA receptors are permeable to Cl- and ECl is -50 to -70 mV so when the GABA receptors open
they are just going to bring the membrane closer to ECl and not closer to the threshold for an AP
○ If Erev < threshold then inhibitory
○ Fast vs Slow Chemical Synapses
 Fast - All previously talked about synapses were fast ones
 Slow (prolonged)
 Usually involves modulation of ion channels
 Process
○ Neurotransmitter binds a metabotropic receptor (see below)
○
○
○
○
G-protein is activated
G-protein subunits or intracellular messengers modulate ion channels
Ion channel opens
Ions flow across membrane
 Basic Neurochemistry
○ Objectives
 Review the following topics
 Process of neurotransmitter release
 Components of the major intracellular signaling pathways in neurons
○ G proteins
○ Secondary messengers (cyclic AMP, diacylglycerol/IP3; Ca/Calmodulin)
○ Protein phosphorylation mechanisms
 Generic issues for neurotransmitters
 Define necessary requirements of neurotransmitters and distinguish these characteristics from those of
neuromodulators
 Compare the different types of neurotransmitter receptors with regard to:
○ Location - pre and postsynaptic
○ Functional relationship to ion channels
○ Neurochemical effector systems
○ Structure (subunit composition & membrane conformation)
 List the neurotransmitters with multiple receptor subtypes and their effects on neurons
 Specific classes of neurotransmitters
 Acetylcholine
○ Describe process for synthesis and degredation
○ Describe types of acetylcholine receptor
○ Pathophysiology - myasthenia gravis, sarin attack
 Neuroactive amines, the catecholamines and serotonin
○ Discuss the chemistry and synthesis of dopamine, norepinephrine and epinephrine
○ Discuss the role of MAO and COMT in neurotransmitter breakdown
○ Describe the major classes of pharmacological agents that interact with catecholaminergic and
serotonergic systems
○ Compare the synthetic and degredative pathways for serotonin to those of the catecholamines
○ Pathophysiology - parkinson’s and schizophrenic symptoms with long term treatment of PD
 Amino Acid Transmitters (and one-step modifications)
○ Discuss the metabolism of GABA: synthesis, degredation and the GABA shunt
○ Describe the types of GABA receptors and the mechanism of action of the benzodiazepines
○ Summarize the evidence that glycine is a neurotransmitter in the spinal cord
○ Describe the role of glutamate as an excitatory neurotransmitter in the CNS
○ Discuss the involvement of NMDA receptors in long-term potentiation (LTP)
 Peptide Neurotransmitters
○ Distinguish the action of peptides in the CNS from the more classic forms of neuroendocrine regulation:
neurosecretion and releasing factors
○ Characterize substance P and methionine-enkephalin and provide evidence that they act as
neurotransmitters
○ Determine the precursor/product relationships that exist between proopiomelanocortin (POMC),
proenkephalin A and the opiate peptides
 Discuss the major diseases associated with neurotransmitters
○ Ca is required for transmitter release
○ If some K channels blocked, then AP spike is prolonged
○ Postsynaptic Receptors
 Ionotropic - ligand-gated ion channels
 Fast onset, short acting, fEPSPs or fIPSPs
 Each subunit has 3 or 4 transmembrane domains
 Metabotropic - binding of the neurotransmitter alters biochemical processes in the recipient cell.
 Late onset, long lasting
 Amplifies original signal
 7 transmembrane domains (on a single peptide) coupled with G proteins
 Process - G Proteins coupling receptors to ion channel
α subunit of G protein binds GDP
Receptor binds neurotransmitter
receptor/neurotransmitter binds to G protein
α subunit replaces GDP with GTP, α dissociates from rest of G protein and becomes activated
Activated α subunit activates the ion channel by activating an effector cell or doing it directly
○ α subunit continues to be active until GTP is hydrolyzed
○
○
○
○
○
 Classes of G Proteins
G Protein
Gs (stimulatory)
Gi (inhibitory)
Gq/Gp
Go (other)
Second Messenger
Effector
Target
cAMP upregulated
cAMP downregulated
DAG (diacylglycerol)
and others
none
↑ adenylate cyclase
↓ adenylyl cyclase
↑ Phospholipase C
and others
↑ K, Ca channels
directly
Protein Kinase A?
Protein Kinase A?
Protein Kinase C
and ER Receptor
○ Gp, PIP2 and Phospholipase C go on to produce IP3 (which goes to ER and releases Ca) and
DAG (which is membrane bound and activates Protein Kinase C)
○ Calmodulin - has 4 calcium binding sites and regulates multiple enzymes
○ Neurotransmitters
 3 Key Properties
 Stored in a presynaptic vesicle
 Released in a Ca dependent manner and interacts with a membrane bound receptor
 Physiological action mimicked by agonists and blocked by antagonists
○ Physiological action also mimicked by experimental addition of the neurotransmitter
 If they don’t fill these properties then they are neuromodulators
 Biosynthesis of Neurotransmitters
 Small molecule neurotransmitters
○ Amino acids or derivatives of them
○ Enzymes to make them originate in nucleus, undergo post-translation modification in the cell
body and then transported to the axon terminals
○ Transmitters then made in terminals and also packaged there
○ In EM look clear
 Peptide neurotransmitters
○ Originate from cleavage of peptide precursors within the rough ER and Golgi
 Packaged into vesicles from there and transported to axon terminals
○ In EM are large dense vesicles
 Transmitter Receptors on Neurons
 Locations
○ Normal - Postsynaptic receptor on soma
○ Autoreceptor - presynaptic terminal that releases A also has receptor for A
 These are often inhibitory
○ Heteroreceptor - presynaptic terminal releases A but also has receptor for B, which is released
by another neuron
 This is called presynaptic inhibition
 Specificity of Action
○ The specificity of response for a neurotransmitter is determined by the nature of the receptor that
is activated
○ do we need to know the following table???
○
Neurotransmitter
Dopamine
(metabotropic)
Norepinephrine
(metabotropic)
Acetylcholine
GABA
Glutamate
Receptor Type
Effect
D1 or D5
D2, D3, D4
α1
α2
β
Nicotinic
Muscarinic
M1, m3, m5
M2, m4
↑ adenylyl cyclase
↓ adenylyl cyclase
↑ Phospholipase C
↓ adenylyl cyclase
↑ adenylyl cyclase
Na/K conductance
GABA A (fast acting)
GABA C (slow acting)
GABA B
AMPA/Kainic Acid
NMDA
Metabotropic
↑ Phospholipase C
↓ adenylyl cyclase
G protein coupling to ion channel
Cl conductance
Cl conductance
K/Ca conductance
(G protein coupled)
Na/K conductance
Ca conductance
↑ Phospholipase C
○ Chemistry of Selected Neurotransmitters
 Acetylcholine
 Synthesis via choline acetyltransferase
○ Acetyl coenzyme A + Choline → Acetylecholine
 Degredation via acetylcholinesterase, not degredation
○ Acetylcholine → acetate + choline
 Receptors
○ Effects depend on which type of receptor (though the agonist is not normally present, they are
still named after them)
○ Nicotinic
 Agonist = Nicotine
Antagonist = Curare
 Location - NMJ in the brain
 Ligand-gated ion channel that is fast (fEPSP) and excitatory
○ Muscarinic
 Agonist = Muscarine
Antagonist = Atropine
 Location - brain
 G-protein coupled receptors that are slow and either excitatory or inhibitory
○ M1, m3, m5 receptors are excitatory and work via increasing PKC activity via DAG
○ M2 and M4 receptors are inhibitory and work via decreasing the cAMP
○ Antagonists - interfere with the binding of the agonist; bind at the site that the agonist would
bind to
 Clinical Correlations
○ Myesthenia Gravis - autoimmune disease against nicotinic receptors of skeletal muscle cells
○ Sarin gas - a nerve poison that works by inhibiting acetylcholinesterase and thus causing
overstimulation of the neuron (excitotoxicity)
 Catecholamines and Serotonin
 Structure
○
 Synthesis of Catecholamines
○ Tyrosine hydroxylase - rate limiting step (thus is complexly regulated)
 Requires pteridine cofactor
○ DOPA decarboxylase - requires pyridoxal phosphate
○ Dopamine β-hydroxylase - contains Cu and is located in synaptic granules
○ Phenylethanolamine-N-methyltransferase - requires SAM
○ Do we need to know cofactors??? They weren’t mentioned in class

 DOPA can cross blood/brain barrier, dopamine can’t because it is charged
 Synthesis can stop at dopamine, norepi, or epi
○ Degredation of Catecholamines
 Inactivated by reuptake if not immediately put into a vesicle then degraded
 Enzymatic degredation
○ Monoamine oxidase (MAO) - bound to the outer mitochondrial membrane
○ COMT - requires SAM and Mg. located in the cytoplasm
○ Products of these enzymes show up in the urine
○ Pharmacology
Drug
Neuroleptic (haloperidol)
Tricyclic antidepressants and cocaine
MAO inhibitor
Amphetamine
Functional Action
Antipsychotic
Antidepressants
Antidepressant
Stimulant and antidepressant
Neurochemical Action
Blockade of catecholamine receptors
Blocks reuptake from synaptic cleft
Inhibition of MAO
Inhibitor of MAO; inhibits reuptake from synaptic cleft
 ↑ availability → mood enhancer
 ↓ availability → depressant
 Synthesis of Serotonin
○ See picture on right
○ Broken down by MAO
 GABA
 Synthesis and metabolism
○ Synthesized from glutamate
○ Since the synthesis of GABA pulls one
α-ketoglutarate out of the TCA cylce,
which could produce 1 GTP that could
be turned into ATP
 so you lose one ATP for every GABA made???
○
 GABA Receptors
○ GABAA - ionotropic, ligand gated Cl channels
 Benzodiazepines (valium and Librium) enhance binding of GABA to its receptor
 Blocked by bicuculline
○ GABAB - metabotropic, G protein linked Ca and K channels
○ GABAC - ionotropic, ligand gated Cl channels, but slow
 Glycine
 Synthesized from serine
 Resembles GABA in its effects on Cl permeability (compare to GABA)
 Blocked by strychnine
 Glutamate
 Powerful excitatory neurotransmitter (excitotoxic in excess)
 Subtypes: AMPA, Kainate, NMDA and mGluR1-mGluR5
 NMDA Subtype
○ Gated by Mg+
○ If stimulus is long enough, then enough positive charge will enter through glutamate activated
Na channel and will cause the positively charged Mg to leave
○ Then Ca can come in and ‘do’ long-term potentiation, which is involved in memory formation
 Causes ↑ in AMPA receptors on postsynaptic membrane
 Phosphorylation of transcription factors (like CREB) to regulate gene transcription and
increase synthesis of proteins that modify synaptic structure
○ Is the only glutamate activated channel to let Ca in
○ Peptide Neurotransmitters and Modulators
 Neurosecretion
 Neurons in the posterior pituitary etc can release peptides (like oxytocin) when stimulated via nerve
impulses
 Regulation of anterior pituitary function
 Neurons in the anterior pituitary release hormones when stimulated by regulatory substances
released from the hypothalamus
 Peptides as neurotransmitters
 Substance P
○ High concentrations in areas involved in pain regulation
○ Localized with methionine-enkephalin and serotonin
○ Mediates pain perception in the spinal cord
○ Localized to dorsal horn of spinal cord, specifically made in DRG?
 Opiate Peptides
 Types
○ Enkephalins - 5 AA peptides that vary on their last AA with either methionine-enkephalin and
leucine-enkephalin
○ β-endorphin - 30 AA
○ Dynorphin
○ Opiate receptor antagonist - naloxone
 Synthesis
○ Enkephalins
 Pre-proenkephalin A → proenkephalin A → multiple met-enkephalin + leu-enkephalin
○ β-Endorphin
 Pre-pro-opiomelanocortin → pro-opiomelanocortin → ACTH + β-lipotrophin (which
becomes γ??)
 γ-lipotrophin + β-endorphin
○ Dynorphin
 Made from prodynorphin
 Expressed in the caudate putamen and the basal ganglia ?
 Opoid Receptors
○ All three are G protein coupled and inhibit adenylate cyclase, which increases hyperpolarization
via K channels and decreases calcium influx through Ca channels
○ Pathological Conditions





Parkinson’s - Loss of dopamine in the nigral-striatal system
Schizophrenia - overactivity of dopamine in the mesolimbic and mesocortical systems
Alzheimer’s - loss of cholinergic cells of the nucleus basalis
Huntington’s - loss of GABA-ergic and cholinergic cells of the striatum
Myasthenia gravis - autoimmune response directed against the acetylcholine receptor in the
neuromuscular junction
 Organization of the Cerebral Cortex
○ Objectives
 Explain why the cerebral cortex is important
 Point out the locations and size differences of the neocortex and allocortex
 Describe the arrangement of the cerebral cortex on the outside of the cerebral hemispheres, and the arrangement
of lobes, gyri and sulci
 Describe the morphology and functions of the types of neurons and glia in the cortex
 Identify the names and arrangement of the 6 neocortical layers
 Describe structures that provide direct inputs (afferents) to neocortex and targets of direct neocortical outputs
(efferents)
 Explain the distinction between a cortical neurotransmitter and neuromodulator and identify cortical components
associated with amino acid transmitters and agents that function as transmitters or modulators
 Summarize understanding of how many cortical areas exist in the human brain and the general arrangement of
primary sensory, primary motor and higher order cortical areas
 Describe the basic organization of a cortical column as a cortical information processing unit
 Explain the concepts of cortical serial and parallel processing
 Identify locations of allocortex components in the hemisphere
 Present a basic understanding of neurogenesis in the adult human cortex
○ Neocortex - makes up 90% of brain
 Has 6 layers of cells
 Drastically bigger in humans
 Neuropil - brain tissue with high density of axon terminals, cell bodies and dendrites
 Tracts - collections of axons in the brain (white matter)
 Sulci - infoldings, Fissures are large sulci
 Gyri - cortical matter between infoldings
 Types of Cells
 Neurons
○ Pyramidal Cells - most numerous, pyramid
shaped, large efferent neurons
 Think of organization in columns
○ Apical dendrite - goes to surface of cortex
○ Basal dendrite - extend radially
○ Axon projects to subcortical white matter
○ Granule (stellate) cells - less numerous, star
shaped, small interneurons
 Dendrites are short and highly branched
extending in all directions
 Axons end locally
 Glial Cells
○ Macroglia
 Astrocytes - star-shaped with numerous
process, maintain ionic balance etc.
 Oligodendrocytes - numerous processes,
produce myelin for axons of CNS
○ Microglia
 Small phagocytic cells of different shapes
 Cortical Circulation
 See right
 Neocortical Layers (Laminar Architecture)
 Layers are determined by relative density and composition of cells
 Supragranular
○ I - molecular layer (has few cell bodies, mainly axons and dendrites)
○ II - external granular layer
○ III - external pyramidal layer
 Granular
○ IV - internal granular layer
 Infragranular
○ V - internal pyramidal layer
○ VI - multiform layer (has variably shaped pyramidal
neurons)
 Cortical Inputs
 Cortex - ex. from ipsalateral (same side) or contralateral
cortex
 Subcortex - ex. claustrum and nucleus basalis
 Diencephalon - ex. thalamus, tuberomammillary nucleus
 Brainstem structures - ex. ventral tegmentum, locus
ceruleus raphe complex
 What do we need to know here???
○ See picture on right
 Distributions of input terminations in cortex
○ Different patterns of laminar distribution are seen in
different cortical areas
○ What do we need to know here???
○ See picture on right
 Output (Efferent Projections) From Neocortex)
 Output neurons of the neocortex are pyramidal cells and
they terminate in other cortical areas,
subcortically or in the spinal cord
 Neurons in supragranular layers - typically
project to other cortical areas
 Neurons in infragranular layers - typically
project to subcortical areas and other
cortical areas
 Neurochemical Transmission in the
Neocortex
 A given transmitter or modulator has
multiple receptors
 A given neuron has multiple receptors for
multiple transmitters or neuromodulators
 Neuromodulators are weak, slow and long acting
 Fast and short acting (neurotransmitters) - glutamate,
GABA (the amino acids)
○ All thalamic inputs to cortex are excitatory and release glutamate
 Agents that can be both neuromodulators and/or neurotransmitters
○ Acetylcholine - released from nucleus basalis
○ Amines - (serotonin, noradrenaline) raise excitability
○ Peptides - (vasoactive intestinal peptide (VIP)) excitatory transmitters
 Mapping the Cortical Areas
 Popular maps of the cortical areas are based on the fact that the appearance of the 6 cortical laminae
(layers) varies in a predictable pattern based on location
 Granular Cortex - is found in primary sensory cortical areas and has a high density of granule
neurons
 Agranular Cortex - is found in the primary motor cortex and premotor cortex because it has a
high density of pyramidal cells
 All other areas have an arrangement
somewhere in between those two
 Cortical Columns
 Serial Processing
 Parallel Processing
○ Allocortex
 makes up 10% of brain and has < 6 layers of
cells
 Paleocortex
 On ventral surface of the frontal and
temporal lobes
 Contributes to the sense of smell and to the function of the limbic system
 Skipped some structure names that were also skipped in class
 Archicortex (hippocampal formation)
 Located in the temporal lobe
 Includes the dentate gyrus, hippocampus, and subiculum
 Has only three layers instead of the 6 in the neocortex
 Contributes to memory and emotional responses
○ Neurogenesis in Adults
 New cells, specifically granule cells, are generated in the dentate gyrus of the archicortex
 These new cells are generated from neural stem cells near the ventricles
 Principles of Neurological Imaging
○ Objectives




Review the Technology
Understand the basic principles underlying the various modalities
Identify the general capabilities and limitations to the various imaging methods
For each modality know:
 What is the probe or energy used to acquire the image information
 What property of the tissue or subject is expressed in the image
 What general clinical areas is this useful
 Basic image quality and artifacts
 Basic elements of risk
○ Ionizing Radiation Hazards
 Deterministic Effects - if you get a certain dose then this will happen
 Ex. Erythema, epliation, cell death etc. shouldn’t happen at diagnostic levels
 Stochastic Effects - if you get a certain dose then this could happen
 Ex. Cancer (main risk), risk compounds with dose
○ Ultrasound
 High frequency compression (sound) waves
 Echo Imaging - sound reflects from boundaries
 Does not easily pass through air?? or bone, used mainly for body imaging, carotid arteries etc.
 Can show cysts, stones, structures
 Doppler Imaging - if the ping comes back at a different frequency then the stuff is moving
 This shows blood flow
○ X-Rays
 Transmission imaging - x-rays go through structures and the shadow of what makes it to other side
(what is attenuated) is what shows up on the image
 Attenuation is a function of thickness, material density and atomic number
 Detectors - usually the x-rays excite a medium which then exposes the film so that a smaller dose of xray can be used
 Radiography - the normal one shot x-rays
 Fluoroscopy - dynamic x-rays
 Disadvantages
 Limited ability to see soft tissue differences
○ Improved by using contrast media, iodine for vasculature and barium for GI tract (just subtract
out the precontrast background)
 Ionizing radiation (rips off electrons)
○ CT (Computed Tomography)
 Obtains x-ray density of thin cross-sections from many angles then uses a mathematical algorithm to
see tissue differences with density differences of 0.5%
 X-Ray gun rotates very fast around patient
 CT Number - related to ability of material to stop the radiation
 - = less dense than water and black, 0 = water, + = more dense than water and white
○ soft tissue near 0
 Contrast media - iodine for either blood vessels or GI
 Spiral CT - when doing whole body CT the imager just spirals down the body and never gets and exact
horizontal cut. Math is used to get that
 Perfusion imaging - can see how fast your contrast media flows into a location
○ Nuclear Medicine
 Emmision technique
 Give patient a radioactively labeled substance (ex. radioactive iodine to image thyroid, or radioactive
sugar to image areas of high metabolic activity) and then view were it is deposited in the body
 You learn physiological things instead of anatomical things
 Disadvantages
 You give ionizing radiation
 Low resolution, noisy images
 Can be planar images or tomographic images (where multiples 2D slices make a 3D representation)
 SPECT - Single Photon Emission Computed Tomography
○ Uses gamma emitting radionuclides
 PET - Positron Emission Tomography
○ Uses positron emitters
○ Has better uniformity and resolution
○ Positron - like an electron, but with a positive charge
 When combined with an electron they annihilate and cause the release of two photons in
opposite directions
○ These pairs of photons are detected and the location of the positrons are calculated
 PET/CT - Lay a CT over a PET and get benefits of both
○ MRI (Magnetic Resonance Imaging)
 Explanation???
 H atoms have a dipole and thus when they are put in a magnetic field they will line up with that
magnetic field
○ They line up in the parallel or antiparallel state, but they don’t line up directly exactly, they line
up at an angle and they don’t stay in one spot, they wobble along an axis (the wobble is the
Lamour frequency?)
 The higher the magnetic strength, the greater the wobble
○ Radio frequency alters some of the nuclei’s wobble and when this wobble goes back to normal it
is detected?
 How fast it goes back to normal is different for different tissues and thus can be interpreted
 Gadolinium based contrast agents can be used (not used for people with kidney problems)
 Things that are Measured to Produce an Image
 ρ - proton density - relative number of available hydrogen nuclei
 T1 - Spin-Lattice Relaxation - relative rate that excited nuclei return to the ground state (which is
aligned with the magnetic field)
○ Fluid is black and Time to Echo (TE), Repetition Time (TR) are short
 T2 - Spin-Spin Relaxation - the rate that proton precessing (wobble) in synchrony go out of phase
○ Fluid is white and TE, TR are long
 Special MRI Scan Methods
 FLAIR - fluid attenuated - minimizes signal from CSF and edema
 Diffusion MRI - looks water’s ability to diffuse (in strokes, it has decreased ability)
 Perfusion MRI - often used with gadolinium contrast, looks at ability of blood to perfuse
 Functional MRI - visualize change in blood flow
○ BOLD - Blood Oxygen Level Dependent - the difference between oxygenated hemoglobin and
deoxygenated hemoglobin can be determined in and this is what is used to create the fMRI
 MR Spectroscopy - allows the analysis of the chemical environment of hydrogen atoms in vivo
 Can determine chemical profile of meningioma etc.
 MRI Hazards
 Strong magnetic field (0.2-0.3T) Always On
 Magnetic fields can cause nerve stimulation
 Radio frequencies can cause heating
 Somatosensory System 1
○ Objectives
 Explain what the somatosensory system is and what it does
 Point out the 4 somatosensory modalities of body feeling and the adequate stimuli for each
 Describe the receptors that transducer somatosensory stimuli and indicate where different receptors are located
in the body wall
 Explain events underlying transduction by receptors
 Explain steps involved in initiation of action potentials
 Point out two ways that stimulus intensity is encoded by primary sensory fibers
 Explain what a receptive field is, how it contributes to localization of feelings and how receptive field size
varies across receptors
 Point out the difference between rapidly and slowly adapting fibers, give examples of each type of fiber and
explain their contributions to detecting rapidly and slowly changing stimuli
 Point out differences between different classes of A fibers and between A and C fibers in terms of sensory
modality, conduction velocity, diameter, myelination and associated receptor types
 Explain what the labeled line principle is and 3 factors which contribute to the labeled line modality specificity
of a sensory fiber
 Describe how inflammation can sensitize primary sensory neurons
 Describe outcomes of sensory fiber regeneration after injury and give examples of problems that may arise from
regeneration
○ Function of Somatosensory System
 4 modalities of conscious sensory information




Touch - can be discriminative or crude (feel of muscle ache)
Propioception - body position and movement
Temperature - warmth or cold
Pain - impending or actual damage of tissues
○ Can be due to mechanical, chemical or thermal factors
 Other conscious feelings are derivatives of these
 Sensory information can also be subconscious (reflexes, irregular body functions etc)
○ Stimulus occurs in body, but the feeling occurs in the cortex via processing
○ Somatosensory Receptors = primary sensory neurons
 Are pseudounipolar with a distal axon receiving input and a central axon sending it
 Distal axon can be associated with a non-neural end organ
○ End Organs
Sensory Modality
Discriminitive
Touch
Crude Touch
Proprioception
Temperature
Pain
Receptor Type
Meissner Corpuscle
Pacinian Corpuscle
Merkel Receptor
Ruffini Corpuscle
Hair Folicle
Free Nerve Ending
Muscle spindle
Joint Receptors
(Ruffini Corpuscle,
Pacinian Corpuscle)
Golgi Tendon Organ
Free Nerve Endings
Free Nerve Endings
Body Wall Location
Skin
Skin, Viscera
Muscle
Joints
Tendons
Skin
Most Tissue
 Each type of receptor is generally located at a different depth of the body wall
 Density of receptors varies in different skin locations
 The difference in two-point discrimination threshold at different skin locations is partly due to the
different densities of touch receptors, especially merkel and meissner
○ Stimulus Transduction
 Ion channels in mechanoreceptors are stimulated by stretch or displacement; chemoreceptors by the
appropriate ligand; thermoreceptors by heat
○ Receptive Field
 Meissner and merkel cells have small receptive fields
 Stimulus Intensity Encoded by
 Frequency of AP in single fibers
 Number of activated fibers
○ Adaptation
 Rapidly Adapting Receptors
 APs fire at stimulus onset, but not during continuation of stimulus
 Useful for stimuli that change rapidly (ex. vibration)
 Slowly Adapting Receptors
 APs fire at stimulus onset and during continuation of stimulus
 Useful for stimuli that are present for long periods of time (ex. continuous stretch of a muscle)
○ Types of Primary Sensory Fibers
Receptor Type
Muscle Spindle
Golgi Tendon Organ
Meissner Corpuscle
Pacinian Corpuscle
Merkel Receptor
Ruffini Corpuscle
Hair Follicle
Free Nerve Ending
Sensory
Fiber Class
Aα, Aβ
Aα, Aβ
Aβ
Aβ
Aβ
Aβ
Aβ
Aδ, C
Receptor-Sensory
Fiber Adaptation
Slow
Slow
Rapid
Rapid
Slow
Slow
Rapid
Slow
Threshold
Low
Low
Low
Low
Low
Low
Low
High (for pain)
Low (for temp)
 Fibers with fastest conduction rates are associated with proprioception, then touch, then temp, pain and
crude touch
 Only pain fibers have high thresholds
○ Labeled Line Principle - sensory fibers are specialized to transmit info about only one modality
 Three factors contribute to this
 Type of receptor (mechano, thermo, etc)
 Location of nerve endings - nerve endings for proprioception and touch both have
mechanoreceptors, but because they are in different places, they are interpreted differently
 Threshold - nerve endings for touch and pain both have mechanoreceptors, but pain ones have
higher threshold
○ Inflammation and Peripheral Sensitization
 Inflammation can cause the sensation of more pain with less stimulus due to peripheral sensitization
 Inflammation releases substances which can
 Cause the direct activation of receptors
 Increased receptor sensitivity
 Decreased thresholds for voltage activated channels, thus facilitating APs
 Ex. - PGE2 is a molecule released with inflammation, it binds to EP2 receptors on the distal ends of
pain fibers, which ↑ cAMP, which then activates PKA, which then ↑ sensitivity of voltage-gated Na
channels, thus makes it easier for them to open and easier for APs to occur
○ Regeneration of Sensory Axons
 The distal end of the axon that is still connected to the cell body can regenerate slowly
 But it doesn’t have a good way to find the place that it is supposed to be regenerating to (thus can
lead to abnormal sensations)
 Neuroma - when large numbers of regenerating nerves migrate back to the cell body
 Somatosensory System 2
○ Objectives
 Outline the peripheral organization of primary somatosensory neurons in spinal and cranial nerves, ganglia and
roots as they project to spinal or brainstem levels of the CNS
 Describe receptive field innervation territories of cranial nerves to the face, peripheral nerves to the hand and
dorsal root dermatomes to the body
 Describe the major divisions of the spinal cord grey and white matter
 Describe the locations in the medulla of the dorsal column nuclei, solitary nucleus and trigeminal nuclei
 Describe the major central termination zones of primary sensory neurons
 Explain the modality organization of central projections and terminations of primary sensory neurons
 Explain the somatotopic organization of central projections and terminations of primary sensory neurons
 Explain how abnormal insertion of receptor-ion channel complexes into membranes of primary sensory neurons
contributes to sensory changes after injury
○ How Primary Sensory Neurons Enter CNS
 Injury or disease of PNS structures will alter body feelings on the same side as the injury or disease
 Also since all modalities travel together in PNS structures if a PNS structure is injured then all
modalities will be affected
 Distal axons of primary sensory neurons that enter Spinal Cord
 Pathway - Peripheral nerve → plexus → spinal nerve → DRG → dorsal root
 Plexi
○ Cervical Plexus - C1-C5
Brachial Plexus - C5-T1
no plexi - T2-T12
○ Lumbar Plexus - L1-L4
Sacral Plexus - L4-S3
 Innervation from viscera
○ Pathway - viscera → prevertebral ganglion → splanchnic nerve → paravertebral sympathetic
chain ganglia → spinal nerve → DRG (where cell body is) → dorsal root
 Distal axons of primary sensory neurons that enter Brainstem
Nerve
Body Region
Peripheral
CNS Tract
CNS
Enters
Ganglion
Termination
Brainstem
Zone
Spinal Nerves
V - Trigeminal
(ophth, max,
mandibular)
VII - Facial
IX Glossopharyngeal
X - Vagus
Lissauer’s tract
Spinal grey
Dorsal column
Dorsal column
nuclei
Main and spinal
trigeminal nuclei
Back of head, neck
and body
Dorsal root ganglia
Face, mouth
Trigeminal ganglia
Trigeminal
Pinna, auditory canal,
eardrum
Pinna, auditory canal,
eardrum
Oral and nasal cavity,
pharynx, carotid sinus
Pinna, auditory
cannal, eardrum
Thoracic and
abdominal viscera
Geniculate ganglia
Trigeminal
Superior ganglia
Trigeminal
Inferior (petrosal)
ganglia
Jugular (superior)
ganglia
Nodose (inferior)
ganglia
Solitary
Trigeminal
Solitary
at lateral pons
Spinal trigeminal
nuclei
Spinal trigeminal
nuclei
Solitary Nucleus
at jnx of pons
and medulla
at medulla
Spinal trigeminal
nuclei
Solitary nucleus
at medulla
○ Receptive Fields
 Innervation Territory - receptive field of a group of sensory neurons (ie. peripheral nerves)
 Dermatome - sum of the receptive fields of all the sensory axons in one dorsal root
 Innervation territories of peripheral nerves and dermatomes do not always correspond due to
regroupings of fibers in an intervening plexus
○ Spinal Cord Structure
 Grey - dorsal, intermediate and ventral horns
can be divided into lamina
 White - dorsal, lateral and anterior columns
 Lissaeur’s tract - between the dorsal and
lateral columns where dorsal root attaches to
spinal cord
○ Brain Stem Structure
 See picture on right
○ Termination Zones of the Central Axons
of the Primary Sensory Neurons

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
Spinal Grey
Dorsal Column Nuclei (Gracile and Cuneate Nuclei)
Main Trigeminal Nucleus
Spinal Trigeminal Nuclei
Solitary Nucleus
 Recheck notes here
○ The entire primary sensory neuron, distal to central
axon stays on one side of the body
○ Modality Organization of Primary Sensory Neurons to Termination Zones
 In PNS, sensory neurons of all modalities travel together, when they enter the CNS they split up and
axons of different modalities travel separately and to different places
 Inputs entering spinal cord
 Touch and Propioception (A-α and A-β)
○ Axons enter spinal cord via Lissaur’s tract, go to dorsal column and
 Ascend up dorsal column, travel through cuneate or gracile fascicle and terminate in
respective cuneate or gracile nucleus of the dorsal column nuclei in the medulla
 Branch, leave dorsal column (white matter) and terminate in deep layers (more ventral, not
more caudal) of the spinal grey around the level they entered
 Pain, Temp and Crude Touch (A-δ and C)
○ Axons enter the spinal cord via Lissaur’s tract to the superficial layers of the spinal grey
(dorsal horn) around the level they entered
 Inputs entering brain stem
 Touch and Proprioception
○ Most project into trigeminal tract and terminate
in main trigeminal nucleus
○ Others branch in the trigeminal tract and
terminate in the deeper layers of the spinal
trigeminal nuclei
 Pain, Temp and Crude Touch
○ Enter via cranial roots V, VII, IX (the superior
ganglion only), or X (the superior ganglion only)
then through the trigeminal tract and terminate
in the superficial layers of the spinal trigeminal
nuclei
 Trends
 Face vs body processed differently
 Touch vs pain processed differently
○ Somatotopic Organization
 Adjacent locations of the body or face project to adjacent locations in the CNS
 See picture
○ Injury to Primary Sensory Neurons
 Normally, receptor ion channel proteins of primary sensory neurons are only in the distal-most parts of
the distal axon
 If the distal axon gets chopped off, then new receptor ion channels will be placed, but they often get
misplaced (ectopic insertion) and can lead to the formation of unusual postinjury sensations
(phantom pain, chronic pain)
 Somatosensory System 3
○ Objectives
 Describe simple concepts of integration at somatosensory synapses
 Point out examples of transmitters and modulators used at initial somatosensory synapses
 Describe the major sensory modality, nuclei where synapses are made, tracts through which axons travel and
decussation level for the dorsal column-medial lemniscal, trigeminal lemniscal, anterolateral, and
trigeminothalamic systems
 Explain the basis for modality organization in the ascending systems to primary somatosensory cortex
 Explain major features of somatotopic organization of the ascending systems to primary somatosensory cortex
 Describe levels of the ascending pathways which are regulated by descending systems
 Point out somatosensory functions beyond the production of body feelings
 Point out examples of referred pain and how it is explained
 Describe how local anesthetic blockades work
 Predict sensory changes caused by somatosensory lesions
○ Integration
 When primary sensory inputs connect with secondary ones they can converge or diverge
 Inhibition
 Local Inhibition - synapses from same neuron are made to neuron A and local inhibitory neuron
which then synapses with neuron A
○ The effect is that the signal going to neuron A is effectively reduced
 Descending Inhibition - axons from higher order neurons come down and stimulate inhibitory
neurons which then affect convergence and divergence patterns
○ Ascending Somatosensory Systems
 Things to Note

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Sensory modalities transmitted
Nuclei where synapses are made
Tracts through which axons travel
Decussation
 Trends
 Each system is modality coded and body/face processing is different
 Inputs from one side of the body or face project to the opposite side of the thalamus or cortex
 Inputs from Body (not face)
 Dorsal Column Medial Lemniscal Pathway - touch and proprioceptive signals
○ Primary axons ascend via dorsal columns to secondary neurons @ dorsal column nuclei which
then decussate in medulla (which is at same leve) then ascend via medial lemniscus (through
pons and midbrain) to tertiary neurons @ lateral division of the ventroposterior nucleus
(VPL) (which is in the thalamus) then ascend via internal capsule (a fiber tract) to fourth order
neurons in the primary somatosensory cortex
 Anterolateral (spinothalamic) Pathway - pain, temp and crude touch
○ Three subdivisions: spinothalamic, spinotectal and spinoreticular tracts
○ Primary axons enter through Lissaur’s tract, ascend via spinal grey to secondary neurons @
dorsal horn which then decussate in the spinal cord and ascend via anterior portion of lateral
white columns then
 For spinothalamic tract they travel through medulla pons and midbrain then end in third
order neurons in the lateral division of the VPL, then ascend via interal capsule to fourth
order neurons in the primary somatosensory cortex
 For spinotectal tract second order neurons terminate on third order neurons in the
periaqueductal gray and colliculi in the tectum
 For spinoreticular tract second order neurons terminate on third order neurons in the
reticular formation in the brainstem
 Inputs from Face
 Trigeminal Lemniscal Pathway - touch and proprioceptive signals
○ Primary axons from cranial root V enter trigeminal tract to secondary neurons @ main
trigeminal nucleus which then decussate in the pons and ascend via trigeminal lemniscus
(through pons and midbrain) to tertiary neurons @ medial division of the ventroposterior
nucleus (VPM) (in thalamus) then ascend via internal capsule to fourth order neurons in the
primary somatosensory cortex
 Trigeminothalamic Pathway - pain, temp and crude touch
○ Primary axons from cranial roots V, VII, IX, or X enter trigeminal tract to secondary neurons
@ spinal trigeminal nuclei which then decussate in the medulla and ascend via
trigeminothalamic tract to third order neurons @ medial division of VPM which then ascend
via internal capsule to fourth order neurons in primary somatosensory cortex
○ Somatotopic Organization of Ascending Systems
 Lower Body to Face Map
 Represented lateral to medial in thalamus
 Represented medial to lateral in cortex
 The body map in the dorsal column nuclei (gracile and cuneate) and the face map in the main
trigeminal nucleus merge to form single map in VP nucleus
 Note - even things like the medial lemniscal tracts are somatotopically organized
○ Ascending and Descending Pathway Interaction
 Regulation from Somatosensory cortex descending
pathways
 Pyramidal cell layers V and VI descend and synapse at
each level of the ascending cortex, often with
inhibitory interneurons
 Regulation from brainstem descending pathways
 When periaqueductal gray releases enkephalin it
stimulates raphe and lateral tegmental nucleus to
stimulate the enkephalin interneurons which inhibit
pain signals.
○ This is analgesia
○ He talked about which types of neurons these things
were (adrenergic or serotonergic), see figure
○ Somatosensory System and Subconcious
Spinothalamic tract
 Reflexes - proprioception inputs can go directly to motor
neurons in the spinal grey
 Cerebellar Functions
 Lower limb - proprioception inputs synapse at Clarke’s nucleus in spinal grey and ascend lateral
white column to cerebellum via the dorsospinocerebellar tract
 Upper Limb - proprioception inputs synapse at cuneate nucleus and send axons to cerebellum via
cuneocerebellar tract
 Autonomic Functions - inputs from CN IX and X go to solitary nucleus, which has connections that
go to structures in the brain that control autonomic functions
 Central Arousal - reticular formation regulates arousal for higher brain structures and thus the
spinoreticular tract (a subdivision of the anterolateral system) activates central arousal via pain, temp
and crude touch
○ Referred Pain
 Pain inputs from viscera enter via autonomic structures and synapse on spinothalamic neurons that
receive convergent pain inputs from skin or superficial body regions
○ Examples of Spinal Lesions
○ Local Anesthetics
 Interfere with channel conformation changes that allow opening  Look at the handouts, page 78-81
 Somatosensory System 4
○ Objectives
 Point out the locations of the 4 areas of primary somatosensory cortex
 Point out the names and locations of the cortical components of the processing rout through posterior parietal
cortex
 Point out the names and locations of the cortical components of the processing route through the lateral sulcus
cortex
 Describe two ways that signals from a given body location are processed differently in different cortical areas
 Point out differences in size and laterality of receptive fields of primary sensory neurons versus primary cortical
area 3b neurons versus posterior parietal area 7 neurons, and what this infers about spatial coding
 Explain how body maps of each half of the body are connected
 Expalin ways that cortical representations of the skin are affected by normal use
 Describe changes in cortical maps after injury and after regeneration of nerves
 Point out potential presynaptic and postsynaptic mechanisms that are thought to underlie somatosensory system
plasticity
 Describe difficulties in determining cause and effect relationships between cortical and sensory changes
 Define terms used to refer to disturbances of somatosensory sensation
○ Information processing
 In the primary somatosensory cortex
 Cortex divided into 4 areas (3a, 3b, 1 and 2), each with a separate and different map of the body
and face
 Lower body is medial and upper body is lateral
 Signals are processed from one of the 4 areas to the other.
○ Ex many 3b axons end in area 1
 In higher order cortical areas
 From primary somatosensory cortex → posterior parietal cortex (esp. areas 5, 7, 39 & 40) →
frontal cortex (esp. motor cortex)
 From primary somatosensory cortex → cortical areas in the lateral sulcus (which include the
secondary somatosensory cortex, the insular area and the retroinsular area) → limbic structures
(which include the amygdala and hippocampus)
 Analysis
 While unilateral receptive fields are usual in primary somatosensory areas, in the nonprimary
cortical areas bilateral receptive fields are common
 Different-sized receptive fields and different-sized representations in different cortical areas
indicate these cortical areas are performing different functions
 Hemisphere Interconnectivity
 Connecting each half of the body mainly occurs in the posterior parietal and lateral sulcus cortex
where bilateral receptive fields are more common
○ Plasticity of the Somatosensory System
 Somatotopic organization can change in response to
 Changes in use patterns
○ Ex - increased use and activity from D2 and D3 enlarged cortical maps of those fingers at the
expense of less used fingers
○ Ex - cortical area represeing a Braille reading finger in a Blind person is larger than normal
 Somatosensory and motor cortical areas can be involved
 Injury to the body
○ Ex - hand amputation results in changes to the somatotopic map that bring surrounding
structures on the somatotopic map (the arm and face) closer together. This means that the arm
and face areas actually move and this is believed to be related to phantom pain and allodynia
 Zones in cortical maps that lose normal inputs after peripheral injury acquire substitute inputs
from neighboring body regions that are innervated by adjacent uninjured nerves
 This was an example of a peripheral nerve, but a similar thing happens when a dorsal root or
the spinal cord becomes injured
 Injury and then subsequent regeneration
○ Cortical map changes that appear after injury to a peripheral nerve are reversible if the injured
nerve regenerates and reactivates the cortex
○ Problems
 The substitute inputs from neighboring body regions will often partially persist
 Regenerated inputs will often be smaller than pre-injury inputs
 Cortical maps of regenerated inputs can be abnormal
 Mechanisms for plasticity after injury
 Following injury, somatotopic map plasticity doesn’t only happen in the cortex, it happens
anywhere a somatotopic map can occur (thalamus, brainstem, spinal cord etc)
 After injury, weak connections (dashed lines) can become strong (arrows)

 Mechanism for weak → strong conversion
○ ↑ excitatory transmitter release from neurons of the substitute projection system (R above)
○ ↑ presynaptic terminals (↑ # of synapses) on neurons related to substitute projection system
○ Changes in phosphorylation of receptor proteins, which can increase postsynaptic response
 Cortical Reorganization and Phantom Pain
 High degrees of cortical reorganization of face inputs into hand-forelimb maps correlate with high
levels of phantom pain
○ But this does not imply causation because it could be the amputation itself causing the phantom
pain and the phantom pain causes the cortical reorganization
○ Terms (know them)

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
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
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Allodynia - pain sensation to a stimulus that is normally not painful
Analgesia - loss of pain sensibility
Anesthesia - complete loss of all modalities of sensation
Astereognosis - inability to recognize objects by touch
Atopognosis - inability to localize tactile stimuli
Causalgia - burning pains due to nerve injury, often associated with changes in the appearance of skin or nails
Hypalgesia - diminished sensibility to pain
Hyperalesia - increased sensibility to pain
Hyperesthesia - increased tactile sensibility
Hypesthesia - diminished tactile sensibility
Neuralgia - painful spasms occurring along the distribution of a nerve
Neuritis - toxic, traumatic, or infectious inflammation of a nerve, characterized by pain or tenderness in the
receptive field of the nerve
 Paresthesia - spontaneously occurring abnormal numbness, tingling or prickling sensations
○ Lesion Examples
 LOOK AT THEM
 Neurochemistry 3 (Alzheimer’s and Parkinson’s Disease)
○ Objectives
 Describe epidemiology, behavioral manifestations and major pathological characteristics of Alzheimer’s and
Parkinson’s diseases
 Consider evidence for the causes of Alzheimer’s and Parkinson’s diseases
 Reflect on key differences between these two conditions as well as issues of disease progression, limitations of
current therapy in efficacy and potential for adverse events, and new therapies or means of early detection
○ Alzheimer’s Disease
 By delaying AD by 5 years you can half the cost and prevalence
 First to go is recent memory, then cognitive decline, progressive degeneration
 Neuropathology
 Amyloid Plaques - extracellular deposit of amyloid
 Neurofibrillary tangles - intracellular helical deposits that eventually fill cell and kill it
 Cholinergic deficit in nucleus basalis
 Generalized neuronal loss due to apoptosis as disease progresses
○ Hippocampal cell loss
○ Reduced cortical thickness, narrowing of gyri and deepening of sulci
○ Cell loss is associated with metabolic decreases in brain
 Theories of Alzheimer’s Disease


Infectious Agent Theory - prions cause similar symptoms, but pathology is different (not spongiform)
Toxin Theory - Aluminum is secondary to the primary cause of AD
 Abnormal Protein Theory
○ (Neurofibrilary Tangle Formation) Tau - a microtubule associated protein whose
hyperphosphorylation correlates with formation of neurofibrilary tangles
 the cell’s machinery can’t clear the hyperphosphorylated protein
○ (Plaque Formation) β-Amyloid - a toxic protein created by the abnormal cleavage of amyloid
precursor protein (a transmembrane protein (APP)) by β-secretase and γ-secretase
 APP is on CH 21 and normally only cleaved by α-secretase to form the normal sAPPα
 Mutations that make APP more likely to be cleaved to form β-amyloid are bad
 Genetic Theory
○ Down syndrome always gets AD - results from gene dosage effect
○ Late-onset AD - correlated with apolipoprotein E4 on CH 19
○ Familial AD - 25% of cases
 Can be mutations that make APP more likely to be cleaved to β-amyloid
 Association with presenilins, which are associated with γ-secretase activity and promote
formation of β-amyloid
 Acetylcholine Theory
○ Cholinergic neurons in nucleus basalis degenerate in AD
 Neurons from nucleus basalis innervate many higher areas in the brain, and are likely
involved in memory consolidation (thus their degeneration linked to memory deficits)
○ Also innervate hippocampus
○ Aricept - acetycholinesterase inhibitor effective only in early to moderate cases of AD (when
cholinergic cells are still around?)
○ Namenda - glutamate (NMDA) receptor antagonist used for moderate to severe cases of AD to
reduce amount of Ca to nerve cells and prevent secondary processes initiated by Ca (like cell
death) from happening.
 NMDA receptors are involved in long-term potentiation though so inhibiting them would decrease memory
○ Parkinson’s Disease
 Symptoms
 Tremor at rest, muscle and limb rigidity
 Diminished and spontaneous movements
 Bradykinesia - slower voluntary movements (acceleration and velocity)
 Pathology
○
 dopaminergic pathways of the brain in normal condition (left) and Parkinsons Disease (right).
Red (hatched) arrows indicate suppression of the target, blue arrows indicate stimulation of
target structure.
 Note that many pathways are eventually relayed via the thalamus to the motor cortex
○ Substantia nigra - dopaminergic neurons are lost in the substantia nigra (part of brainstem) and
this causes reduced activation from basal ganglia to thalamus to motor cortex
 Therapy
○ L-Dopa - precursor to dopamine
 Must be administered systemically with uptake inhibitor that doesn’t cross blood-brain barrier
○ Pallidotomy - lesioning of the internal division of the globus pallidus thus reducing inhibition to
thalamus
○ Electric Stimulation to Thalamus
 Auditory System
○ Objectives











Diagram the major ascending pathways of the auditory system
Describe the structural features of the middle ear that facilitate transmission of sound to the cochlea
Compare the ionic compositions of the endolymph and perilymph
Describe the process whereby sound vibrations entering the ear are converted to electrical activity and the
auditory nerve
State the approximate numbers of inner and outer hair cells
Describe the relationships of type I and type II auditory nerve fibers to the inner and outer hair cells
Describe how sound frequency and intensity are coded in the cochlea, auditory nerve and cochlear nucleus
Name 3 types of neurons in the cochlear nucleus and describe how their structural specializations are correlated
with their physiological properties
Describe the connections of the superior olivary complex that are involved in spatial localization of a sound
source and explain how sounds can be localized by the functions of these connections
Describe the neural components of the centrifugal pathway from the superior olivary complex to the cochlea
State one key feature of the auditory function of each of the higher auditory centers: inferior colliculus, medial
geniculate nucleus and auditory cortex
○ Major Pathways
 Cochlea → auditory nerve → cochlear nucleus →
 Along trapezoid body to superior olivary
complex
 and/or along lateral lemniscus to inferior
colliculus
 → brachia of inferior colliculus → medial
geniculate body → auditory radiations → auditory
cortex in the superior temporal gyrus (areas 41 and
42)
○ Auditory Stimulus
 Hear frequencies from 20-20000 Hz, differences 2 Hz
 Hear amplitude range in trillions, a logarithmic scale
(thus no ‘real’ zero)
 Greater than 85 dB can cause damage
○ Coding of Sound Stimulus
 Middle Ear - converts air vibrations (registered by
tympanic membrane) → fluid vibrations received
by oval window
 Middle ear bones and muscles reduce these
vibrations significantly
○ Bones - malleus, incus, stapes
○ Muscles - tensor typani connects to malleus,
stapedius connects to stapes
 Eustacian tube - equalizes pressure across tympanic membrane (connects to back of throat)
 Cochlea - converts fluid vibrations → electrical signals
 Fluids - similar to other intra and extracellular fluids except
○ Endolymph - ↑K and ↓Na, Perilymph - ↓K and ↑Na
 Structure
○ Pathway = oval window → scala vestibuli (above organ of corti) → smaller to apex then
switches to scala tympani → larger to round window
○ Scala vestibuli and scala tympani contain perilymph
○ Scala media - which between the other two contains endolymph and its K concentration is kept
↑ by the stria vascularis, this makes a very positive (+80) extracellular environment
○ Organ of Corti - receives vibrations from scala vestibuli
 Structure
○ basilar membrane - below hair cells
○ inner hair cells - 1 row, 4000
○ outer hair cells - 3-4 rows, 20,000
○ tectorial membrane - above hair cells
○ spiral ganglion and auditory nerve fibers send info out to olivocochlear terminals
 Process
○ Fluid vibrations → organ of corti vibrations
 Tonotopic organization - higher frequencies can’t travel as far so they activate more basal
parts (lower, more apical)
 Vibrations bend hair cells → open ion channels → K enters hair cell very quickly (very
positive extracellular environment due to endolymph vs negative intracellular environment)
 K entry leads to depolarization and Ca entry and transmitter release and APs
 Coding
○ Frequency - determined by which part of organ of corti is stimulated
○ Amplitude - determined by amplitude of vibrations and amount of organ vibrating
○ Coded Information to Brain
 Cochlea → auditory nerve → cochlear nucleus → brain
 Neurons - take info from hair cells in specific parts of the cochlea to the cochlear nucleus
 Cell bodies housed in spiral ganglia
 Type I - Bipolar, 90%, myelinated, similar diameter (thus similar speed), end at inner hair cells,
each fiber goes to only a few hair cells
 Type II - Pseudounipolar, 10%, unmyelinated, end at outer hair cells, each fiber goes to many hair
cells
 Action Potentials of Type I fibers
 At rest - spontaneous activity due to leakage of channels
 Sound evoked activity
○ Tuning curve - at successively higher intensities, each fiber responds to a successively wider
range of frequencies
○ APs are synchronized and increase at beginning of stimulus, but plateau (tonic activity) if persist
○ Recoding information in the Cochlear Nucleus
 Cochlear nucleus gets info from auditory nerve and reprocesses it
 Cochlear nucleus divided into three major parts, anteroventral, posteroventral and dorsal cochlear
nucleus.
 Each has its own major type of cell
 Each is organized tonotopically (higher frequencies more dorsally)
 Types of Cells
 Sperical bushy cells - located in AVCN
○ Small dendritic fields; few, large terminals with auditory nerves (not much convergence)
 Responses very similar to auditory nerve, but have better tuning curve
○ Transmit information to superior olivary complex bilaterally
 Octopus Cells - located in the PVCN
○ Large dendritic fields that integrate information from nerve fibers from many frequencies
○ Respond only to beginning of stimulus, thus transmit timing information to superior olivary
complex and nuclei of lateral lemniscus mainly contralaterally
 Fusiform Cells - located in the DCN
○ Large dendritic fields in parallel to auditory nerve fibers (thus still small tuning curve)
 Responses very different from auditory nerve due to lots of inhibition and processing
○ Transmit information to inferior colliculus mainly contralaterally
○ Processing in Superior Olivary Complex
 Codes sound location in space by processing convergence of info from both cochlear nuclei
 Lower Frequency Sounds - localized by time differences
 Lower frequency sounds will reach both ears, they will just do so at different times
 Excitation of spherical bushy cells → excitation of both medial superior olivary nuclei (MSO)
and an MSO’s excitation is best when inputs from both cochlear nuclei stimulate it simulataneously.
 Higher Frequency Sounds - localized by intensity differences
 Higher frequency sounds could be blocked by head and not reach other ear
 Dependent on excitation on lateral superior olivary nucleus (LSO) and its excitation is dependent
on a balance between excitation from the bushy cells of the ipsalateral CN and the inhibition from
medial nucleus of the trapezoid body (MNTB) via the excitation from the bushy cells of the
contralateral CN.

 Olivochochlear Bundle (OCB) - a feedback pathway to cochlea
 Feedback inhibition - activation leads to decreased responses in auditory nerve fibers by repressing
hair cells
 Interestingly transmitter is acetylcholine
○ Higher Auditory Centers
 General Features - Tonotopic, loudness coded by numbers of active neurons, some neurons respond
only to sounds in a specific space
 Inferior Colliculus - in midbrain
 Receives info from cochlear nuclei, superior olives and nuclei of lateral lemniscus (in picture)
 Has detailed map of auditory space and tonotopic organization
 Medial Geniculate - in thalamus
 Receives all info to be sent to auditory cortex
 Has more complex responses, more attention to sounds
 Auditory Cortex - in superior part of temporal lobe
 Binaural interaction - alternation of EE and EI stripes
○ EE Stripe - neurons excited by sound to either ear
○ EI stripe - neurons excited by sound to one ear, inhibited by sound to opposite ear
 Vestibular System
○ Objectives

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
Describe the major pathways of the vestibular system
Describe the fluid spaces of the vestibular labyrinth and their relationship to those of the cochlea
Describe how linear accelerations are converted to electrical activity in the otolith organs
Describe how angular accelerations are converted to electrical activity in the semicircular canals
Describe the reflexes whereby body and eye movements are coordinated with head movements
○ Major Pathways
 In General - vestibular system quickly sends info to regions controlling motor activity without going
through cerebral cortex
 Primary - from vestibular labyrinth (utricle, saccule and ampullae to Scarpa’s ganglion) to
 Ipsilateral vestibular nuclei
○ Medial vestibular nucleus (MVN), Lateral vestibular nucleus (LVN), Superior vestibular
nucleus (SuVN) and Inferior/Spinal vestibular nucleus (IVN/SpVN)
 Ipsalateral cerebellum - nodulus, flocculus and uvula - via juxtarestiform body in inferior
cerebellar peduncle
 Secondary - from vestibular nuclei to
 Cerebellum - nodulus, flocculus and uvula - ipsalaterally via juxtarestiform body
 Nuclei controlling extraocular muscles - via 4 things
○ Medial longitudinal fasciculus (MLF)
○ Abducens (VI nerve), Trochlear (IV nerve) and oculomotor (IIIrd nerve)
 Ventral Horn of Spinal Cord
○ Lateral Vestibulospinal Tract - ipsilateral from lateral vestibular nucleus to facilitate
motoneurons for extensor muscles in both arms and legs
○ Medial Vestibulospinal Tract - bilateral from medial vestibular nucleus mostly to terminate in
cervical levels and affect neck movements
 Other Connections
 To vestibular nuclei from
○ Cerebellar cortex of vermis and flocculus (GABA neurotransmitter)
○ Cerebellar fastigial nucleus
○ Nucleus dorsalis (Clarke’s nucleus) of spinal cord - fibers travel with dorsal spinocerebellar
tract
 From vestibular nuclei to
○ Thalamus → Cortex; Hypothalamus; Reticular formation; Contralateral vestibular nuclei;
Vestibular receptor cells
○ Vestibular Coding of Stimuli
 General
 Hair cells - synapse to vestibular bipolar neurons
○ Type I - flask-shaped with vestibular bipolar neurons connecting with chalice shaped terminals
○ Type II - cylindrical with vestibular bipolar neurons connecting with bouton terminals
 Vestibular bipolar neurons - are irregular because they have inherent spontaneous activity
○ Both small and large are myelinated
○ Large diameter - synapse with Type I and have irregular patterns of spontaneous activity
○ Small diameter - synapse with Type II and have regular patterns of spontaneous activity
 Cilia - hairs on the tops of hair cells
○ Kinocilium - longest cilia, all others get progressively shorter
 Bending of cilia towards kinocilium leads to depolarization and release of excitatory
transmitter (thus stimulation of vestibular bipolar neuron)
○ Remember - tops of hair cells in endolymph
 Thus with cilia cause channels to open, K rushes in (and because bottoms of hair cells
in perilymph with low [K] the K rushes out when it is done)
 Bending of cilia away from kinocilium leads to hyperpolarization and thus no release of
excitatory transmitter
○ Magnitude of change in bipolar neuron discharge rate deponds on the amount of bending
 Otolith Organs
 Utricle and saccule are main structures, receptor cells in macula
 Used for orientation of the head with respect to linear acceleratory forces, including gravity
 All directions of excitation are represented in each macula
 Utricle - macula oriented mainly in horizontal plane
○ Cilia of hair cells embedded in gelatinous material containing otoliths (which have more inertia)
 Saccule - macula oriented mainly in vertical plane
 Semicircular Canals
 Horizontal, superior and posterior canals (at right angles of each other) are main structures, receptor
cells in crista
 Used for orientation during angular movement
 All hair cells in each crista have same orientation of cilia
 Internal Structure and Function
○ Within the ampulla, cilia of hair cells embedded in cupula, which blocks the flow of
endolymphatic fluid
○ Endolymph moves and bends cupula, which bends cilia
○ Movement has same effect on all hair cells in a given channel since they all have same
orientation
 Motion which excites canal on one side inhibits corresponding canal on opposite side
○ Vestibular Reflexes
 Phasic Postural Reflex - automatically leaning when running in a circle (excites extensor muscles)
 Righting Reflex - keeps orientation relative to gravity
 Vestibulo-ocular Reflexes - maintain direction of gaze during movement
 Nystagmus - when tracking something in car, slow movement in one direction followed by rapid
movement (saccade) in opposite direction
 Auditory and Vestibular Disorders
○ Objectives
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Describe 2 tests commonly used to evaluate auditory function
Describe 3 tests commonly used to evaluate vestibular function
Define conductive hearing loss and describe 4 disorders of this type
Define sensorineural hearing loss and describe 7 disorders of this type
Explain the basis for both auditory and vestibular symptoms in disorders of the inner ear
Define vestibular compensation
○ General
 Auditory disorders are often accompanied by vestibular symptoms
 The more peripheral the abnormality the more straight forward it will be
○ Clinical Tests
 Auditory
 Audiogram - measures threshold for each frequency and you can compare bone conduction vs. air
conduction
 Auditory brain stem evoked response - for people who can’t tell you if they can hear
○ Monitor EEG of brainstem and correlate peaks with activity in structures in auditory pathways
 Vestibular
 Balancing Test - stand still with eyes closed to test otolith organs
○ Can stand on foam to minimize somatosensory input
 Barany Test - rotate and Barany chair and monitor eye movements for normal nystagmus
○ Tests each pair of semicircular canals
 Caloric test - only one that you can test each side separately
○ Angle head and put hot or cold water into external ear canal to cool endolymph in a specific
semicircular canal then monitor nystagmus.
○ Conductive Hearing Loss - impaired conduction of sound to cochlea
 Excess wax
 Perforation of tympanic membrane
 Decreased sound transmission across spectrum, self-healing if not too large
 Otitis Media - ear infection and fluid in middle ear
 Impaired movement of middle ear bones due to fluid accumulation
 Danger of spread of infection to brain
 Might have to put ventilating tube into tympanic membrane to allow drainage
 Otosclerosis - spongy bone formation (usually around oval window) leading to impairment of stapes
movement
 May also have tinnitus
 Can treat by stapedectomy where stapes is replaced with an artificial one, but you lose the stapedius
muscle and thus some sound dampening
○ Sensorineural Hearing Loss - impaired cochlea or auditory nerve function
 Often accompanied with vestibular disorder
 Noise Damage - Destruction of hair cells due to loud noise that leads to hearing loss (especially affect
basal turn of cochlea (high frequencies)) and sometimes tinnitus
 no good treatment
 Presbycusis - degeneration of hair cells due to age, especial basal (high frequency) cells
 No good treatment
 Ototoxicity - drug-induced damage to inner ear
 Damage to inner ear, especially basal (high frequency) cells due to drugs like streptomycin,
neomycin, asprin, antitumor etc. (cause unknown)
 No good treatment, just try to catch early since this side effect is seen in some not all
 Labyrinthitis - bacterial or viral infection of the labyrinth
 Can cause vertigo and hearing loss
 Meniere’s Disease
 Increased endolymph pressure (patient can feel it), which leads to vestibular and cochlear
malfunction
 Generally in one ear
 Vestibular Symptoms - spells of vertigo often with nausea, pathological nystagmus
 Auditory Sytmptos - tinnitus, spells of hearing loss most often at lower frequencies
○ Only disorder where you get loss at lower frequencies
 Treatments - antihistamines, shunts to subarachnoid space, destruction of vestibular hair cells with
ototoxic drug, labyrinthectomy or section of vestibular nerve
 Congenital Malformation of Labyrinth
 Often genetic, or can be due to prenatal rubella
 Vestibular dysfunction, hearing loss - can stimulate auditory nerve via cochlear prosthesis
 Eight Nerve Tumors (Acoustic Neuromas)
 Usually a benign tumor which compresses the VIII CN leading to unilateral (typically) hearing loss,
tinnitus, disequilibrium and vertigo
 Remove it
 Blood Supply Problems - Labyrinth blood supply from labyrinthine artery from anterior inferior
cerebellar artery (AICA)
○ Vestibular Compensation - if part of vestibulary system gets damaged via trauma, then you will be
messed up for a bit but then you will make a nice partial recovery
○ Central Hearing Disorders
 More complicated
 Central Tinnitus - cause unknown, but may result from changes in central auditory pathways after
damage to cochlea
 Disorders of brain blood supply
 Brain tumors - may lead to compression of central auditory centers
 Chemical Imbalances
 Olfactory Systems
○ Objectives
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Describe the major pathways of the olfactory system
State the steps and timing of the olfactory receptor cell regeneration
Explain how information about odors is converted to electrical activity in the olfactory epithelium
Describe the organization of the olfactory bulb and neurotransmitters involved
Describe the organization of the olfactory cortex
State possible causes and effects of impaired sense of smell
○ Major Pathways
 All are ipsalateral
 Receptor cells (primary neurons) in olfactory epithelium → secondary neurons in olfactory bulb
 Secondary Neurons project to olfactory cortex regions
 Anterior olfactory nucleus, piriform cortex, olfactory tubercle, cortical nucleus of the
amygdala and the entorhinal cortex
 Higher connections
 Anterior olfactory nucleus → contralateral olfactory bulb
 Piriform cortex & olfactory tubercle → medial dorsal nucleus of thalamus → orbitofrontal cortex
○ Conscious perception
 Piriform cortex & amygdala → hypothalamus & midbrain tegmentum
○ Affective response
 Entorhinal cortex → hippocampus
○ Olfactory Epithelium
 Receptor Cells - have cilia projecting into mucus layer containing receptors to specific odorants
 Have thin unmyelinated axons projecting up to olfactory bulb
 Regenerate continuously
○ Basal cells develop into receptor cells and it takes 60 days to do so
 Each receptor can be activated by several different odorants
○ Wide range of sensitivity - generally lipid-soluble substances identified more easily
○ Adaptation occurs to constant odors
 Transduction of signal requires G protein with secondary messengers of cAMP and IP3
○ Olfactory Bulb (know neurotransmitters)
 Organization of neurons
 Olfactory receptor cells synapse (using carnosine) with mitral cell dendrites at a ratio of 1000:1 in
glomeruli (the functional units for processing odor information)
○ Mitral cell axons project to the olfactory cortex
 Interneurons
○ Periglomerular Cells - located near glomeruli and have inhibitory effects using dopamine and
GABA
○ Granule Cells - lack axons, make dendrodendritic synapses with mitral cells and have inhibitory
effects using GABA
 Other Components
○ Tufted Cells - dendrites in glomeruli and axons in olfactory cortex
○ Efferent/Descending (centrifugal) innervation from
 Ipsalateral basal forebrain - transmitter is acetylcholine
 Contralateral anterior olfactory nucleus
 Ipsalateral olfactory cortex
 Coding of Odors
 Different groups of glomeruli are activated by different odorants, but not in any reasonable pattern
 Olfactory receptor neurons having the same receptor gene project to the same glomerulus
○ Olfactory Cortex
 Structure different from Neocortex
 Has 3-4 lamina instead of the normal 6
 Main ascending input is given to layer I instead of the normal layer IV
 Pyramidal cells have somata in layer II and apical dendrites oriented perpendicular to layers
 Inputs from olfactory bulb end on distal parts of apical dendrites
 Association inputs from other cortical regions end on proximal parts of apical dendrites
 WHAT DOES THIS MEAN??
○ Psychology of Smell
 Smell is very important for taste
 We can’t reconstruct a smell in our mind, but a smell can trigger a memory
○ Olfactory Disorders
 Anosmia - loss of sense of smell (Hyposmia - decreased sense of smell)
 Cause - Mechanical, chemical interference, tumor, trauma to olfactory nerve, loss of receptors
 Effect - loss of interest in eating or unawareness of environmental smell dangers
 Prognosis - could be temporary since olfactory receptor cells can grow back
 Olfactory Hallucinations - generally repugnant ones
 Often precede epileptic seizure of uncus region
 Gustatory System
○ Objectives
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Describe the major pathways of the gustatory system
State the process and time course of taste receptor cell regeneration
Explain how information about tastes is converted to electrical activity in taste buds
State the 4 primary taste modalities, where they are mainly sensed on the tongue and what types of substances
have each taste
 Describe what is known about the coding of taste quality and intensity in the primary neurons of the gustatory
system
 State factors that can affect the tastes of foods
 State 3 factors that can lead to loss of taste sensation
○ Major Pathways
 Primary
 Taste
○ Facial Nerve - rostral 2/3 of tongue → geniculate
ganglion → rostral ipsilateral solitary nucleus
○ Glossopharyngeal Nerve - caudal 1/3 of tongue →
petrosal ganglion → caudal to where facial ends
○ Vagus Nerve - throat area → nodose ganglia →
ipsilateral solitary nucleus caudal to where prev ends
 Somatosensory Sensations from tongue
○ Trigeminal - rostral 2/3 of tongue → ipsilateral spinal
trigeminal nucleus
○ Glossopharyngeal - caudal 1/3 of tongue
 Secondary
 Solitary nucleus → ipsilateral central tegmental tract →
ipsilateral ventral posteromedial nucleus (VPM) of
thalamus
 Higher
 VPM → to ipsilateral insula and frontal operculum
 Side pathway from solitary nucleus eventually combines with olfactory information (I skipped
stuff)
○ Structure of Taste Buds
 Three Types of Papillae
 Fungiform Papillae - mushroom shaped on front 2/3 of tongue scattered about
 Foliate Papillae - grooves near posterior lateral sides of tongue
 Circumvallate Papillae - only a few of these lined up at the back of the tongue (bitter tastes)
 All contain - about 50 receptor cells, supporting cells, basal cells, primary neuron processes
 Continuously Regenerate - basal cells → supporting cells → receptor cells
 Process takes 10 days (less time because there is no axon)
○ Taste physiology
 Taste buds are chemoreceptors
 When chemoreceptors stimulated they depolarize cell but depolarization may be direct or indirect
effect depending on tastant
 Salty - direct entry of Na into receptor cell
 Sour (acids) - decrease in permeability to K (and thus a little depolarization)
 Bitter - binding to G-protein coupled receptors → ↑ IP3 → ↑ intracellular [Ca]
 Sweet - binding to G-protein coupled receptors → ↑ cAMP ↓ permeability to K
 Adaptation occurs when constant stimulus
 Depolarization of receptor cell → ↑ intracellular [Ca] → neurotransmitter release → APs generated in
primary neurons → sent to solitary nucleus
 Nerve fibers are small and unmyelinated and thus slow
 Nerve fibers and taste buds converge and diverge and their receptive fields overlap
 Coding Taste Stimuli
 Stimulus Strength - coded by number of fibers and frequency of APs
 Stimulus Quality
○ Sweet - located at tip of tongue, threshold about 10 mM
○ Salty - located on sides of tongue, threshold about 10 mM
○ Sour - located on side of tongue medially, related to H+ concentration, threshold about .1 mM
○ Bitter - located at back of tongue, threshold about .01 mM
 Taste thresholds vary 20x per person
 Neither receptor cells nor primary neurons are responsive to only one taste modality, thus the CNS
must interpret taste magically
○ Psychology of Taste
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Most ‘tastes’ are combinations of taste bud, tongue somatosensory and olfactory stimulation
Taste can be influenced by internal chemical environment of body
Some differences in taste can be explained by genetics (ex. phenylthiourea (PTC))
Tastes of particular foods can change (ex. due to bad experience, due to aging and losing taste buds)
○ Taste Disorders (hard to separate from olfaction disorders)
 Ageusia - Loss of taste
 Causes - head trauma, loss of taste buds due to aging, lesions to facial or glossopharyngeal nerves
(lesion to facial nerve can happen when messing with middle ear)
 Hallucinations - Lesions in or epileptic seizures in the uncus region of brain can lead to abnormal
taste sensations
 Somatosensory Lesions To Consider
○ Peripheral Nerve section
 Complete section usually
 Loss or Attenuation at same side as lesion
 Loss of ALL modalities (reduced or lost feeling)
○ Complete Spinal Section/Transverse Cord Lesion
 Cut entirely across—Dorsal Column and Anterolateral lesion both sides
 So loss of all 4 modalities on both sides below and below the lesion
 Can still have reflexes
○ Brown-Sequard Syndrome/Hemi-Section of the Spinal Cord
 Ipsilateral loss of touch and Proprioception
 Contralateral loss of Pain, temperature, and crude touch (may not be at same level)
 Both for at and below the lesion (Pain, might be a little lower)
○ Central Cord Syndrome: Syringomyelia—Cyst or Tumor formation in the Central Cord
 So may occur at certain levels, like: T6-T9
 Why only a few levelsWe lose the ventral commisure, that is where the Decussation of axons occurs
(death of cells in central canal)
 Only losing the cross, so Anterolateral and Dorsal Column Tracts are ok.
 So bilateral loss of pain, temperature, and crude touch:
 Above and below the lesion are ok.
○ Central Cord Syndrome: Incomplete Lesions of Anterolateral Tracts (Sacral Sparing)
 Bilateral loss of pain, temperature, and crude touch at or below the level of the lesion.
 Why sacral sparingSacral portions of Anterolateral are most lateral
○ Lateral Medullary Syndrome AKA Wallenberg Syndrome
 Lateral Tegmentum Affected (So motor should be ok)
 Thrombosis is a usual cause—Vertebral most common, possibly PICA
 Ipsilateral loss of Pain, Temperature, and crude touch in face
 Contralateral loss of pain, temperature, and crude touch in body (Occiput, neck, and below)
○ Sciatica (a Peripheral Injury)
 Intervertebral discs are damagedsmall holes for the dorsal roots to enter
 Dorsal root compression due to diminished Intervertebral foramen
 So, areas with Sciatic nerve innervation affected on the same side (All of posterior leg and a majority
of anterior leg: see notes for diagram)
○ Dorsal Root Injury (Only Dorsal root, i.e. C4-C8 Dorsal roots)
 Reduction or Loss of all modalities of sensation related to ipsilateral dermatomes.
○ Bilateral Dorsal Lesion-includes Dorsal column and Dorsal Roots
 Bilateral loss of touch and Proprioception
 We lose the dorsal roots, so anything associated with that level will be lost, in this case lose pain,
temperature, and crude touch from those roots.
 C2-C4 example in class, lose all touch and Proprioception below with pain, temperature, and crude
touch in the Occiput is loss
○ Unilateral Dorsal Lesion—Dorsal Columns (both sides) and One Dorsal Root
 Bilateral loss of touch and Proprioception at and below the level of the lesion.
 Ipsilateral loss of pain, temperature, and crude touch associated with that dorsal root.
○ VP Nucleus of Thalamus Lesion
 Loss of ALL somatosensory modalities contralateral to lesion.
○ Lesions in the Somatosensory Cortex
 First, off there is loss of sensation on the contralateral side of the body.
 Secondly, Somatotopic organization!
 Medial lesionloss of lower limb and body sensation.
 Lateral lesionloss of face sensation