Non-neuronal cells in the CNSNon-neuronal cells in the CNS (glia): 10-100x more abundant

Macroglia:Macroglia: large non-neuronal cells

1. astrocytes (star shaped) –mostly located near axons and dendrites

WHY ???

Functions: a. insulate axons/dendrites (non-myelin sheath)

b. Provide many nutrients for neurons

c. “Astrogliosis”: engulf damaged neurons, degrade them. “glial scar” at injury site

d. Help neurons become “excited” by releasing potassium (K+) under certain conditions

2. Oligodendrocytes: “oligo”… (few dendrites)- found everywhere near neurons

Main functions: INSULATION !!

form myelin sheathcalled “Schwann cells” in peripheral NScalled oligodendrocytes in CNS

3. Radial Glia:

Radial glial cells act as guide wires for the migration of neurons

- long processes,very important for development of brainin embryos/fetuses

- Targets of many substances (ex. alcohol) that are “teratogens”

Nature Reviews: Neuroscience, 2, 287-293

4. Ependymal Cells:

- line walls of cerebral ventricles, make/secrete CSF

- projections (flagella) extend into ventricles and “flutter” to produce motion of CSF so it will leave ventricle

Rabbit lateral ventricl Adapted from Haines, D.E. Neuroanatomy: An atlas of structures, sections, and systems, 5th ed. Lippincott Williams & Wilkins, Baltimore, 2000

Neural activity: Neural activity: how a neuron workshow a neuron works

(1) (1) physical properties of neuronal membranephysical properties of neuronal membrane

(2)(2) presence of ion channels (or receptors) in membranepresence of ion channels (or receptors) in membrane

(3)(3) electrical potential across the membraneelectrical potential across the membrane

WHY DO WE NEED TO KNOW THIS ?!!!!!!!!!!!!!WHY DO WE NEED TO KNOW THIS ?!!!!!!!!!!!!!

(1)(1) neurophysiology correlates with behaviorneurophysiology correlates with behaviorfor many clinical disordersfor many clinical disorders

(2)(2) neurophysiology can produce treatmentsneurophysiology can produce treatments

cell body - axon - dendrites

Definitions:Definitions:

““Ion”: Ion”: a molecule that unequal # of electrons and protons?a molecule that unequal # of electrons and protons?- molecule has positive (+) or negative (-) charge- molecule has positive (+) or negative (-) charge

““Electrical Potential”: difference in concentration of “+” andElectrical Potential”: difference in concentration of “+” and “ “-” charged moleculars inside vs outside neuron-” charged moleculars inside vs outside neuron

Important Ions: Important Ions: Sodium (Na+), Calcium (Ca2+), Potassium (K+), chloride (Cl-)

Neurons communicate by means Neurons communicate by means of an electrical signal called the of an electrical signal called the “Action Potential”“Action Potential”

Action Potentials are based on Action Potentials are based on movements of ions between the movements of ions between the outside and inside of the celloutside and inside of the cell

When an Action Potential occurs a When an Action Potential occurs a chemical message is sent to chemical message is sent to neighboring neuronsneighboring neurons

How neurons communicate:

Action potential is an electrical event inside of a single neuron

-involves movement of ions in or out of neuron

“Neurotransmission” is chemical communication between 2 or more

- involves a neuron release a “neurotransmitter” to contact a nearby neuron(s)

The Neuron MembraneThe Neuron Membrane

Outside

Inside

Physical Properties of Membrane

* lipid bilayer- provides control of what gets in

1.not permeable to water or most anything else.

-exceptions ?-exceptions ?

2. non-rigid

ion channelsNeurotransmitter receptors

Properties of Ion Channels and Receptors:Properties of Ion Channels and Receptors:

1)1) proteins proteins extend from extracellular to intracelluarextend from extracellular to intracelluar

2)2) highly specific for particular ionshighly specific for particular ions

3)3) opening and closing are tightly regulatedopening and closing are tightly regulated

open only in specific situationsopen only in specific situations

Electrical Potential Across Membrane:Electrical Potential Across Membrane:

* difference in * difference in ++ vs vs -- charge from charge fromoutside to inside of celloutside to inside of cell

axonaxon

recording electroderecording electrode

extracellular fluidextracellular fluid

reference electrodereference electrode

Cell Membrane “at rest”

K+

Na+ Cl-K+ -

Outside of Neuron

Inside of Neuron

Na+ Cl-

Potassium: more inside than outsideSodium: more outside than insideChloride: more outside than insideCalcium: more outside than inside

Ca2+

Ca2+

Negatively (-) chargedProteins

- Lots of these !!!

***** ***** Negative Resting PotentialNegative Resting Potential ***** *****

Expressed in “milliVolts (mV)”Expressed in “milliVolts (mV)”

what is the potential ?what is the potential ?

why is it negative ?why is it negative ?

resting potential is close to resting potential is close to potential needed to “fire” = neurotransmitter releasepotential needed to “fire” = neurotransmitter release

How does it stay near the resting potential ?How does it stay near the resting potential ?

1.1. Potassium equilibrium potentialPotassium equilibrium potential2.2. Na-K+ exchangerNa-K+ exchanger3.3. Inward rectifying K+ channels and CaInward rectifying K+ channels and Ca2+ 2+ channels ?channels ?

Most ions only get into a neuron if a membrane receptor or ionMost ions only get into a neuron if a membrane receptor or ionchannel open, don’t flow across neuron membrane freely…channel open, don’t flow across neuron membrane freely…

1 ion does flow in and out of neuron along its1 ion does flow in and out of neuron along its““concentration gradient” : ion easily crosses membrane accordingconcentration gradient” : ion easily crosses membrane according

- 70 mV

Large negatively charged proteins

Neurons don’t want most ions to flow across the concentrationgradient because that would cause constant electrical activity andeventual neuron death…

1. K+ equilibrium potential: only K+ flows across membrane1. K+ equilibrium potential: only K+ flows across membrane according to the concentration according to the concentration gradientgradient

*** Other ions only get in when receptors *** Other ions only get in when receptors or channels are forced openor channels are forced open

At rest, more K+ outside of cell – so K+ wants to flow out At rest, more K+ outside of cell – so K+ wants to flow out to equalize intra- and extracellular concentrations. to equalize intra- and extracellular concentrations.

But, as K+ flows out of cell, inside becomes more negative But, as K+ flows out of cell, inside becomes more negative (because of large intracellular proteins). This negative (because of large intracellular proteins). This negative charge attracts K+ charge attracts K+

remember, opposites attract !!remember, opposites attract !!

So, the resting membrane potential represents the balance So, the resting membrane potential represents the balance betweenbetween

1. K+ wanting to flow out of cell because of concentration 1. K+ wanting to flow out of cell because of concentration gradientgradient

2. negative proteins attracting K+ to stay in cell2. negative proteins attracting K+ to stay in cell

2. Na-K+ exchanger2. Na-K+ exchanger: some sodium (Na) does leak into the cell, at all times.

So, neurons have a “pump” that pushes Na+ back out of the cell when concentrations get too high (which can happen in a matter of minutes)

So, why doesn’t this Na outflow make inside even more negative ??

K+ comes in through the same pump that ejects Na

http://pharma2010.wordpress.com/2008/09/08/chemical-synapes/

3. Inward “rectification” of K+ levels:

“K+ channels that primarily allow K+ in cells only under specific conditions…”

-serve a very specific function, maintaining the membrane at rest.

What Happens when the potential is changed ?

(1) Depolarizing stimulus - reduced potential

at -50 mV, Action Potential

what drives the action potential ?

Na+ channels open for millisecondsat +40 mV, these close

K+ outflow repolarizes the potential* small undershoot

A neuron either is more or less likely to fire

How does the action potential have an effect ?

propagation- action potential progresses downthe cell membrane by segments.

one region is stimulated, then the region next to it is, etc.

electrical current changes shape of channels in adjacent regions * Na+ channels

where does this occur ??

cell body

axon

dendritesAxon hillock

Axonal properties of propagation:

(1) voltage-sensitive Na+ channels

(2) where are these Na+ channels ?

myelin nodes of Ranvier

saltatory conduction- “jumping”

Axon (magnified)

At rest the inside of the cell is at -70 mVAt rest the inside of the cell is at -70 mV With inputs to dendrites inside becomes With inputs to dendrites inside becomes

more positive more positive if resting potential rises above threshold if resting potential rises above threshold

an action potential starts to travel from an action potential starts to travel from cell body down the axoncell body down the axon

Figure shows resting axon being Figure shows resting axon being approached by an APapproached by an AP

Dr. Wayne ShebilskeWright State University

Depolarization ahead of APDepolarization ahead of AP

AP opens cell membrane to allow sodium AP opens cell membrane to allow sodium (NA+) in(NA+) in

inside of cell rapidly becomes more positive inside of cell rapidly becomes more positive than outsidethan outside

this depolarization travels down the axon as this depolarization travels down the axon as leading edge of the APleading edge of the AP

Dr. Wayne ShebilskeWright State University

Repolarization follows Repolarization follows

After depolarization potassium (K+) After depolarization potassium (K+) moves out restoring the inside to a moves out restoring the inside to a negative voltagenegative voltage

This is called repolarizationThis is called repolarization

Dr. Wayne ShebilskeWright State University

Finally, HyperpolarizationFinally, Hyperpolarization

Repolarization leads to a voltage below the Repolarization leads to a voltage below the resting potential, called hyperpolarizationresting potential, called hyperpolarization

Now neuron cannot produce a new action Now neuron cannot produce a new action potentialpotential

This is the refractory periodThis is the refractory period

What else might cause a What else might cause a “hyperpolarization” ?“hyperpolarization” ?

Dr. Wayne ShebilskeWright State University

What happens when the current gets to the end of axon ?

electrical vs. chemical communication between neuronselectrical vs. chemical communication between neurons

Otto Loewi- Otto Loewi- using isolated frog heart in physiological fluidusing isolated frog heart in physiological fluidelectric stimulation slowed it downelectric stimulation slowed it down

applied fluid to another frog heartapplied fluid to another frog heartslowed it downslowed it down

A.A. B.B.

CaCa2+2+CaCa2+2+

C.C.

A. nerve impulse arrives at terminalA. nerve impulse arrives at terminaldeforms voltage gates Cadeforms voltage gates Ca2+2+ channels channels

B. CaB. Ca2+2+ flows in flows in microtubules attached to vesicles contractmicrotubules attached to vesicles contractvesicle fuse with terminal membranevesicle fuse with terminal membrane

C. vesicles burst, release neurotransmitter in synaptic cleftC. vesicles burst, release neurotransmitter in synaptic cleft

How does neurotransmitter release change membrane How does neurotransmitter release change membrane potential of another cell ?potential of another cell ?

cell bodycell body

axonaxon

dendritesdendrites

Presynaptic terminal ends at a body, axon or dendritePresynaptic terminal ends at a body, axon or dendritea receptor protein for NT must be presenta receptor protein for NT must be present

1. excitatory post-synaptic potential (EPSP) 1. excitatory post-synaptic potential (EPSP) NT-receptor interactionNT-receptor interaction causes small depolarization causes small depolarization

-70-70

00

mV

mV

-50-50

Spatial SummationSpatial Summation

Temporal SummationTemporal Summation

2. inhibitory post-synaptic potential (IPSP) 2. inhibitory post-synaptic potential (IPSP) NT-receptor interaction causes NT-receptor interaction causes

hyperpolarizationhyperpolarization

-70-70

00

mV

mV

-50-50

Why an EPSP or an IPSP ?Why an EPSP or an IPSP ?

1. neurotransmitter.1. neurotransmitter.acetylcholine, dopamine, serotonin,acetylcholine, dopamine, serotonin,norepinephrine, glutamate, GABAnorepinephrine, glutamate, GABA

2. specific type of receptor2. specific type of receptorone neurotransmitter can produceone neurotransmitter can producean EPSP or an IPSP, depending on receptoran EPSP or an IPSP, depending on receptor

EPSP EPSP IPSPIPSP NaNa++ , Ca , Ca2+ 2+ or Kor K++ ClCl--

Receptor can be an ion channelReceptor can be an ion channel

binding sitebinding site

Ionotropic ReceptorsIonotropic Receptors are comprised of:are comprised of:

1. multiple subunits1. multiple subunitsdifferent proteins link togetherdifferent proteins link together

2. a core which is permeable to 2. a core which is permeable to one or a few ionsone or a few ions

3. binding site on extracellular portion3. binding site on extracellular portion

characteristics: characteristics: fast acting fast acting brief in duration brief in duration

Either excitatory or inhibitoryEither excitatory or inhibitory

Inhibitory Ionotropic Receptors:Inhibitory Ionotropic Receptors: IPSP, Cl IPSP, Cl--

Drugs of abuse ???Drugs of abuse ???

ethanol - barbiturates - benzodiazepinesethanol - barbiturates - benzodiazepines Excitatory Ionotropic Receptors Excitatory Ionotropic Receptors : Na+, K+ ,Ca: Na+, K+ ,Ca2+2+

- nicotine ? - nicotine ?

IIII. . Metabotropic ReceptorsMetabotropic Receptors

G proteinsG proteins(guanine nucleotide binding)(guanine nucleotide binding)

Metabotropic Receptors areMetabotropic Receptors are comprised of: comprised of:

1. a single polypeptide 2. binds to G proteins1. a single polypeptide 2. binds to G proteins

3. binding site 3. binding site

1. G proteins “1. G proteins “αα” subunit “breaks off when NT binds”” subunit “breaks off when NT binds”2.2.activate second messengers , binds to other receptors,activate second messengers , binds to other receptors, binds to ion channelsbinds to ion channels

Characteristics:Characteristics:slow actingslow actinglonger in durationlonger in duration

Either excitatory or inhibitoryEither excitatory or inhibitory

What happens to Neurotransmitter after What happens to Neurotransmitter after Acting at Postsynaptic Site ?Acting at Postsynaptic Site ?

1. enzymatic 1. enzymatic breakdownbreakdown

used to makeused to makemore NTmore NT

2. re-uptake by2. re-uptake by transportertransporter

reabsorbed byreabsorbed byvesiclesvesicles

efficient - takes more energy to start over efficient - takes more energy to start over essential amino acidsessential amino acidsenzymatic processesenzymatic processes

Serotonin Serotonin (5-hydroxytryptamine or 5-HT)(5-hydroxytryptamine or 5-HT)

reuptake is a major focus of drug development effortreuptake is a major focus of drug development effort

WHY ??WHY ??

Some peculiarities of actions Some peculiarities of actions potentials potentials

Not all neurons “fire” at same potential ( -50 mV)Not all neurons “fire” at same potential ( -50 mV)

1. 1. neurons with larger axons require less neurons with larger axons require less depolarizationdepolarization

-specialized to carry information -specialized to carry information more rapidly ??more rapidly ??

2. some granule cells release small amounts 2. some granule cells release small amounts of transmitter without having action of transmitter without having action potentials potentials (do have small depolarization)(do have small depolarization)

3. 3. in some neurons, Na doesn’t drive the in some neurons, Na doesn’t drive the “spike” of the action potential- it’s Ca“spike” of the action potential- it’s Ca2+2+

5.5. Most action potentials last for less than ½ Most action potentials last for less than ½ of a msec , but some action potentials are of a msec , but some action potentials are slow to develop and last minutes slow to develop and last minutes

6. “Gap Junctions”- exceptions to the “chemical synapse”6. “Gap Junctions”- exceptions to the “chemical synapse”

1.1. Close physical contactClose physical contact

2.2. Electrical current decaysElectrical current decays in cell 2in cell 2

3.3. Current bi-directionalCurrent bi-directional (usually)(usually)

4. Speed of transmission ?4. Speed of transmission ? Speed of response “Speed of response “

5. Where do you see these ?5. Where do you see these ?

NeurotransmittersNeurotransmitters

AcetylcholineAcetylcholine SerotoninSerotonin NorepinephrineNorepinephrine DopamineDopamine EndorphinsEndorphins GABA GABA GlutamateGlutamate

-Synthesized in neurons, stored in synaptic vesiclesSynthesized in neurons, stored in synaptic vesicles

-Release by an Action PotentialRelease by an Action Potential

-Activate receptors on another neuronActivate receptors on another neuron

-on dendrites, soma, or axonson dendrites, soma, or axons

Acetylcholine Acetylcholine (ACh)(ACh) Found in “neuromuscular Found in “neuromuscular

junction”junction”

- here motor nerves touch - here motor nerves touch musclemuscle

Involved in muscle Involved in muscle movements andmovements and

function of involuntary function of involuntary musclesmuscles

- breathing, heart - breathing, heart muscle activitymuscle activity

CurareCurare - blocks ACh - blocks ACh receptorsreceptors paralysis resultsparalysis results

Nerve gases Nerve gases and and Black Black Widow spider Widow spider venom - too venom - too much ACh leads to severe much ACh leads to severe muscle spasms and possible muscle spasms and possible deathdeath

Why are acetylcholine receptors important ??Why are acetylcholine receptors important ??

Cigarettes - Cigarettes - nicotinenicotine works on ACh receptorsworks on ACh receptors can artificially stimulate can artificially stimulate

skeletal muscles, leading to skeletal muscles, leading to slight, trembling slight, trembling movementsmovements

Can also increase heart Can also increase heart rate, breathing raterate, breathing rate

Alzheimer’s DiseaseAlzheimer’s Disease

Deterioration of Deterioration of memory, reasoning memory, reasoning and language skillsand language skills

Symptoms may be Symptoms may be due to due to loss of ACh loss of ACh neuronsneurons

Basal forebrainBasal forebrain

Basal forebrainBasal forebrain– sends axons to cortex, hippocampus– sends axons to cortex, hippocampus

Cognition, judgement,Cognition, judgement,Reflexes, sensory processesReflexes, sensory processes

ponspons

medullamedulla

midbrainmidbrain

Where is it ?

Serotonin (5-HT)Serotonin (5-HT)

Involved in Involved in sleepsleep

cause drowsinesscause drowsiness

Involved in Involved in depressiondepression

SSRI’sSSRI’s (selective serotonin reuptake (selective serotonin reuptake

inhibitors) inhibitors) works by keeping works by keeping serotonin in the synapse serotonin in the synapse longer, giving it more time longer, giving it more time to exert an effectto exert an effect

Involved in Involved in sexual behavior sexual behavior increasing serotonin in increasing serotonin in

one one brainstem nucleus brainstem nucleus = = loss of loss of

sexual sexual sensationsensation

Raphe nucleiRaphe nuclei

Raphe nucleiRaphe nuclei: : project to thalamusproject to thalamus basal gangliabasal ganglia hippocampushippocampus cortexcortex

Cognition, motor function, mood, sensory processingCognition, motor function, mood, sensory processing

Where is it ?

Norepinephrine (NE) Norepinephrine (NE) (aka. “adrenaline” )(aka. “adrenaline” )

“ “Fight or flight” responseFight or flight” response

released from released from adrenal adrenal glandgland

AND made by AND made by neuronsneurons

both a neurotransmitter and both a neurotransmitter and

a hormone a hormone

- any substance released by a gland into the - any substance released by a gland into the

bloodstreambloodstream

Arousal = a brain stem Arousal = a brain stem nucleusnucleus

in “reticular formation” in “reticular formation” influencesinfluences

your cogntive arousalyour cogntive arousal

Locus coeruleusLocus coeruleus

Locus coeruleusLocus coeruleus – projects to basal ganglia – projects to basal ganglia hippocampushippocampus

cortexcortex

Cognition, memory, motor function…Cognition, memory, motor function…

Where is it ?

Dopamine (DA) Dopamine (DA)

Involved in Involved in movementmovement, , attentionattention and and learninglearning

Loss of dopamine- Loss of dopamine- producing neurons is producing neurons is cause of Parkinson’s cause of Parkinson’s DiseaseDisease

Dopamine imbalance also Dopamine imbalance also involved in involved in schizophreniaschizophrenia

Required to experience Required to experience “pleasure”“pleasure”

- - “meso-limbic” DA “meso-limbic” DA systemsystem

Neurons in midbrain, send axons to forebrain (limbic Neurons in midbrain, send axons to forebrain (limbic system), release DA system), release DA

Midbrain limbic system

Meso-limbo-corticalMeso-limbo-cortical

Mes-striatalMes-striatal

Meso-limbo-corticalMeso-limbo-cortical: : projects to nucleus accumbesprojects to nucleus accumbes cortex cortex hippocampushippocampus

Meso-striatalMeso-striatal: : projects toprojects to striatumstriatum

Drug reward, cognition, memory, sensory processes…Drug reward, cognition, memory, sensory processes…

MovementMovement

Where is it ?

EndorphinsEndorphins - - part of brains normal response to part of brains normal response to painpain Control pain and pleasureControl pain and pleasure

Released in response to Released in response to painpain

Morphine and codeine Morphine and codeine work on endorphin work on endorphin receptors Involved in receptors Involved in healing effects of healing effects of acupunctureacupuncture

Everywhere in the Everywhere in the brain !!!brain !!!

Gamma-Aminobutyric Gamma-Aminobutyric Acid (GABA)Acid (GABA)

Main inhibitory Main inhibitory neurotransmitterneurotransmitter

Benzodiazepines (which Benzodiazepines (which include tranquilizers such include tranquilizers such as Valium) and alcohol as Valium) and alcohol work on GABA receptor work on GABA receptor complexes complexes

Everywhere in the brain !!Everywhere in the brain !!

GlutamateGlutamate

Major excitatory Major excitatory neurotransmitterneurotransmitter

Too much glutamate (and too Too much glutamate (and too little GABA) associated with little GABA) associated with epileptic seizuresepileptic seizures

Everywhere in the brain !!!Everywhere in the brain !!!

Very important for Very important for learning/memorylearning/memory

HormonesHormones Chemical messengers Chemical messengers

secreted into bloodstreamsecreted into bloodstream

Hormonal communication

Endocrine cells

Blood-stream

Targetcells

Hormones vs. Hormones vs. NeurotransmittersNeurotransmitters

Distance traveled between Distance traveled between release and target sitesrelease and target sites hormones travel longer hormones travel longer

distances (feet)distances (feet) neurotransmitters - travel neurotransmitters - travel

across a synaptic cleft (20 across a synaptic cleft (20 nm)nm)

Speed of communicationSpeed of communication hormones - slower hormones - slower

communicationcommunication neurotransmitters - rapid, neurotransmitters - rapid,

specific actionspecific action

HormonesHormones Released by Released by organsorgans, ,

including the stomach, including the stomach, intestines, kidneys and intestines, kidneys and the even neuronsthe even neurons

Also released by a set of Also released by a set of glands called the glands called the endocrine systemendocrine system

Includes:Includes: hypothalamushypothalamus pituitary glandpituitary gland adrenal glands adrenal glands thyroid glandthyroid gland parathyroid glandsparathyroid glands pineal glandpineal gland pancreaspancreas ovaries and testesovaries and testes

Hypothalamus and Hypothalamus and HormonesHormones Hypothalamus releases Hypothalamus releases releasing releasing

factors factors which in turn cause which in turn cause pituitary gland to release pituitary gland to release trophic trophic hormoneshormones

““releasing hormone” = always from hypothalamusreleasing hormone” = always from hypothalamus

““trophic hormone” = always from pituitary gland, trophic hormone” = always from pituitary gland, causescauses

other glands to release hormonesother glands to release hormones

- adrenal, ovaries, testes, thyroid, …- adrenal, ovaries, testes, thyroid, …

- sexual maturation, sexual behavior, sexual maturation, sexual behavior, growthgrowth

of bones and soft tissue, water/salt of bones and soft tissue, water/salt balance, metabolism, breast balance, metabolism, breast feeding…feeding…