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

○ V

I

RG

1 (G= conductance)

○ 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

V

QC

○ 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 Ca

2+

○ 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)

○ 1

2log58

X

X

zEx (z=valence)

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

cesisaxoplasmic

eraxonDiametcesismembranetlengthCons

tanRe

tanRetan

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 Axon Diameter Myelin Thickness Conduction Speed

Ia and Ib 12-20 +++ 70-120

II 5-14 ++ 25-70

III (A-delta) 2-7 + 10-30

IV (C fibers) .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 Electrical Chemical

Distance between pre and

postsynaptic

3.5 nm 30-50 nm

Cytoplasmic continuity? Yes No

Ultrastructural components Gap junction channels

(connexons)

Presynaptic active zones and vesicles;

postsynaptic receptors

Agent of transmission Ionic current Chemical transmitter

Synaptic delay Virtually absent Significant; at least .3 ms, usually 1-5 ms

Direction of transmission Usually bidirectional, can be

unidirectional

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 Second Messenger Effector Target

Gs (stimulatory) cAMP upregulated ↑ adenylate cyclase Protein Kinase A?

Gi (inhibitory) cAMP downregulated ↓ adenylyl cyclase Protein Kinase A?

Gq/Gp DAG (diacylglycerol) and others

↑ Phospholipase C

and others

Protein Kinase C and ER Receptor

Go (other) none ↑ K, Ca channels

directly

○ 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 Receptor Type Effect

Dopamine

(metabotropic)

D1 or D5 ↑ adenylyl cyclase

D2, D3, D4 ↓ adenylyl cyclase

Norepinephrine

(metabotropic)

α1 ↑ Phospholipase C

α2 ↓ adenylyl cyclase

β ↑ adenylyl cyclase

Acetylcholine

Nicotinic Na/K conductance

Muscarinic

M1, m3, m5 ↑ Phospholipase C

M2, m4 ↓ adenylyl cyclase

G protein coupling to ion channel

GABA

GABA A (fast acting) Cl conductance

GABA C (slow acting) Cl conductance

GABA B K/Ca conductance

(G protein coupled)

Glutamate

AMPA/Kainic Acid Na/K conductance

NMDA Ca conductance

Metabotropic ↑ 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 Functional Action Neurochemical Action

Neuroleptic (haloperidol) Antipsychotic Blockade of catecholamine receptors

Tricyclic antidepressants and cocaine Antidepressants Blocks reuptake from synaptic cleft

MAO inhibitor Antidepressant Inhibition of MAO

Amphetamine Stimulant and antidepressant 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 x-

ray 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 Receptor Type Body Wall Location

Discriminitive

Touch

Meissner Corpuscle

Pacinian Corpuscle Merkel Receptor

Ruffini Corpuscle

Hair Folicle

Skin

Crude Touch Free Nerve Ending Skin, Viscera

Proprioception

Muscle spindle Muscle

Joint Receptors

(Ruffini Corpuscle,

Pacinian Corpuscle)

Joints

Golgi Tendon Organ Tendons

Temperature Free Nerve Endings Skin

Pain Free Nerve Endings 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 Sensory

Fiber Class

Receptor-Sensory

Fiber Adaptation

Threshold

Muscle Spindle Aα, Aβ Slow Low

Golgi Tendon Organ Aα, Aβ Slow Low

Meissner Corpuscle Aβ Rapid Low

Pacinian Corpuscle Aβ Rapid Low

Merkel Receptor Aβ Slow Low

Ruffini Corpuscle Aβ Slow Low

Hair Follicle Aβ Rapid Low

Free Nerve Ending Aδ, C Slow 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

Ganglion

CNS Tract CNS

Termination

Zone

Enters

Brainstem

Spinal Nerves

Back of head, neck

and body

Dorsal root ganglia Lissauer‟s tract Spinal grey

Dorsal column Dorsal column

nuclei

V - Trigeminal

(ophth, max,

mandibular)

Face, mouth Trigeminal ganglia Trigeminal Main and spinal

trigeminal nuclei

at lateral pons

VII - Facial Pinna, auditory canal,

eardrum

Geniculate ganglia Trigeminal Spinal trigeminal

nuclei

at jnx of pons

and medulla

IX -

Glossopharyngeal

Pinna, auditory canal,

eardrum

Superior ganglia Trigeminal Spinal trigeminal

nuclei

at medulla

Oral and nasal cavity,

pharynx, carotid sinus

Inferior (petrosal)

ganglia

Solitary Solitary Nucleus

X - Vagus

Pinna, auditory

cannal, eardrum

Jugular (superior)

ganglia

Trigeminal Spinal trigeminal

nuclei

at medulla

Thoracic and

abdominal viscera

Nodose (inferior)

ganglia

Solitary Solitary nucleus

○ 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 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

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 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

○ Local Anesthetics Interfere with channel conformation changes that allow opening

Spinothalamic tract

○ Examples of Spinal Lesions

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) 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 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 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 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 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 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 levelsWe 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 sparingSacral 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 damagedsmall 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 lesionloss of lower limb and body sensation.

Lateral lesionloss of face sensation