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OSU / Neuroscience / NEUROSC 3000 / What are the glutamate receptors?

What are the glutamate receptors?

What are the glutamate receptors?

Description

School: Ohio State University
Department: Neuroscience
Course: Cellular and Molecular Neuroscience
Professor: Robert boyd
Term: Summer 2015
Tags: neuro 3000, Study Guide, test two, midterm two, chapter 6, chapter 7, Chapter 8, 6, 7, 8, and Neuro
Cost: 50
Name: Neuro 3000 Test Two Study Guide
Description: Covers chapters 6, 7, and 8. Outlined notes come from lectures, the professor's powerpoints, and the chapters in the textbook. Includes images for better understanding. I stayed up all night so you wouldn't have to. Happy studying!
Uploaded: 11/12/2015
46 Pages 149 Views 1 Unlocks
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1


What are the glutamate receptors?



Chapter 6: Neurotransmitter Systems

Victoria Gonzalez

Learning Objectives:

∙ Understand how neurotransmitters are identified and localized

∙ Know how the major neurotransmitters are synthesized

∙ Understand   the   structure   and   function   of   the   major   groups   of   ligand­gated receptors

∙ Understand the structure and function of G­protein coupled receptors

1. Introduction

a. The first neurotransmitter identified was acetylcholine (Otto Loewi) b. The term cholinergic was introduced to describe cells that produce and  release acetylcholine (Henry Dale)

c. Noradrenergic: neurons that use the amine neurotransmitter 


Dopa is converted into dopamine by what?



norepinephrine (Henry Dale)

d. Glutamatergic: synapses that use glutamate

e. GABAergic: synapses that use GABA

f. Peptigergic: synapses that use peptides

2. Studying neurotransmitter systems

a. Criteria for being considered a neurotransmitter:

i. Molecule must be synthesized and stored in the presynaptic neuron ii. The molecule must be released by the presynaptic axon terminal in response to stimulation

iii. When experimentally applied, the molecule must produce a 

response in the postsynaptic cell mimicking the response produced  Don't forget about the age old question of Where is the insertion of supraspinatus ?

by the release of neurotransmitter from the presynaptic neuron

b. To study: molecule must be synthesized & stored in presynaptic neuron i. Immunocytochemistry: make antibodies to specific transmitters  or enzymes which synthesize the transmitter


The amine neurotransmitter serotonin is also called?



1. Used to localize particular molecules to particular cells

2. Neurotransmitter is injected under skin or into bloodstream 

3. An immune response is stimulated—antibodies are made 

and tagged with fluorescent /radioactive markers

4. Antibodies bind to the antigen (neurotransmitter or 

enzymes that make the neurotransmitter)

5. Antibody tags light up parts of the brain where the 

neurotransmitter is present

6. Best antibodies: bind tightly to antigen and not to other 

chemicals in the brain

a. Antibodies for enzymes that make neurotransmitters

are better than for the neurotransmitter itself

2

7. To be a neurotransmitter candidate, the neurotransmitter  Don't forget about the age old question of What is the first rule in insider reporting and trading under section 16b?

and its synthesizing enzyme must be contained in the same 

neuron

ii. In situ hybridization: confirms that a cell synthesizes a particular  protein or peptide

1. If a sequence of nucleic acids is known for a particular 

protein, a complementary strand of mRNA is synthesized 

in a lab

2. The lab synthesized mRNA probe is labeled with a 

radioactive marker; it sticks to the complementary strand of

mRNA

3. To see the cells with the markers, brain tissue is laid on a 

sheet of special film sensitive to radioactive emissions 

(autoradiography)

4. Radioactive cells are visible as clysters of white dots 

Don't forget about the age old question of How to find the extreme values of f(x) = x2+2x-2 [-2,2]?
Don't forget about the age old question of What is self-­esteem?
If you want to learn more check out What is the ideal school size for adolescents?

c. To study: the molecule must be released by the presynaptic axon terminal  upon stimulation

i. Transmitter release is difficult to study; we cannot be sure that the  transmitter was released from synaptic terminals; they might have 

been released as a secondary consequence of synaptic activation

ii. Fluid near the axons or cells can be tested for a substance after the  neuron has been stimulated (Loewi and Dale)

iii. CNS synapses using different neurotransmitters are proximally  close; a single population of synapses cannot be stimulated

iv. Brain slices are kept alive in vitro and soaked in a solution of high  K+ and Ca2+ 

1. High K+ concentration causes depolarization (action 

potential) and stimulates release

2. High Ca2+ concentrations expel neurotransmitters from 

presynaptic axons

v. Optogenetics: used to control signaling in individual neurons We also discuss several other topics like Who are the three main gods of hindu?

1. Specific neurons are excited in the cell to see if 

neurotransmitters are released

d.

3

e. To study: when applied experimentally, the molecule must produce a  response in the postsynaptic cell that mimics the response produced by the release of neurotransmitter from the presynaptic neuron

i. Microiontophoresis: assesses the postsynaptic actions of a 

transmitter

1. Neurotransmitter is dissolved into solution

2. Solution is injected into cell axon before the postsynaptic 

neuron

3. To administer very small amounts, an electrical current is 

run through the micropipette

4. A microelectrode in the postsynaptic neuron can be used to 

measure the effects of the transmitter on the membrane 

potential

5. A neurotransmitter must mimic the effects of the 

transmitter released at the synapse

f. Studying neurotransmitter receptors

i. Each neurotransmitter can bind to various receptor subtypes

ii. Two different neurotransmitters (ex: Ach, GABA) can’t bind to the same receptor

iii. Neuropharmacology: uses agonists and antagonists to classify  receptor subtypes

iv. Agonist: compound that mimics action of neurotransmitter and  stimulates receptor

v. Antagonists: blocks action of normal neurotransmitter and inhibits receptors

vi. Skeletal and heart muscle respond differently to various 

cholinergic drugs

1. Nicotine is an agonist in skeletal muscles; has no effect on 

heart

2. Muscarine is an agonist in the heart; has no effect on 

skeletal muscle

3. Acetylcholine and muscarine slow heart rate

vii. Glutamate receptors: AMPA, NMDA, Kainate

1. Glutamate neurotransmitter binds at all three receptor 

subtypes

2. Each agonist only binds to their respective receptor

a. AMPA only binds to AMPA receptor

b. NMDA only binds to NMDA receptor

c. Kainate only binds to kainate receptor

g.

4

h. Ligand­binding methods

i. Ligand: any chemical compound that binds to a specific site on a  receptor

ii. Ling­binding method: use labeled ligands to bind specifically to  receptors

1. Important for mapping anatomical distribution of 

neurotransmitter receptors in the brain

iii. Ligand can be the neurotransmitter, agonist, antagonist

iv. Ligands can be toxins or components of venom (snails, snakes,  spiders)

i. Molecular analysis

i. Cloning of many receptor cDNAs

ii. Each receptor has five subunits which can be made up of a variety  of polypeptides

iii. Diversity of subtypes are larger than expected because of binding  and pharmacology

3. Neurotransmitter chemistry

a. Most neurotransmitters are:

i. Amino acids

ii. Amines made from amino acids

iii. Peptides made from amino acids

b. Dale’s principle: a neuron only has one neurotransmitter

i. Neurons containing peptides violate this idea because they release  a peptide and either an amino acid or an amine

ii. Now we know that there are neurons with dual transmitters

c. Co­transmitters: two or more transmitters that are released from one  nerve terminal

i. But most neurons release a single amino acid or amine 

neurotransmitter

4. Neurotransmitter transport

a. Transport uses ATP (trans­membrane gradients of NA+ or H+) to create  higher concentrations

b. There are two types of transport

c. Neuronal membrane transporter: shuttles transmitter from extracellular  fluid and synaptic cleft and concentrated it up to 10,000 times higher  within the cytosol of the presynaptic terminal

i. Cotransport mechanism is used: 2 sodium ions are carried across  the membrane with one transmitter molecule

d. Vesicular transporter: crams transmitter into vesicles at concentrations  100,000 times higher than in the cytosol

i. Countertransport mechanism is used: a transmitter is traded for  two protons from inside the vesicle

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5. Cholinergic neurons: acetylcholine

a. Acetylcholine is the neurotransmitter at neuromuscular junctions i. Synthesized by all motor neurons in spinal cord and brain stem

b. Choline acetyltransferase (ChAT) is required for synthesis

i. ChAT is only in cholinergic cells so it is a good marker for cells  that use acetylcholine

c. Two major groups of cholinergic neurons in the brain

d. Basal forebrain neurons: learning, memory

i. Degraded during Alzheimer’s

e. Dorsolateral pontine tegmental constellation: excitability of sensory relay  systems

f. In many circuits in the autonomic (involuntary) nervous system g. Choline is taken up from extracellular fluid by a specific transporter h. Uptake is the rate­limiting step, 

i. Alheimer’s treatments involve increasing choline levels

ii. Requires the cotransport of Na+ and Cl 

i. Once in the presynaptic cell, choline and acetyl CoA combine to make  acetylcholine which is then packaged in a vesicle

i. Packaged by VAChT: vesicular acetylcholine transporter

1. Protons enter the vesicle against their concentration 

gradient; using ATP

2. Acetylcholine is countertransported; two protons leave the 

cell and one acetylcholine molecule enters

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j. Acetylcholine is released and binds to acetylcholine receptors

k. acetlycholinesterase (AChE) degrades acetylcholine into choline and  acetic acid in the synaptic cleft (and on axon membranes)

i. 5,000 / second; AChE has one of the fastest catalytic rates

ii. Made by some cholinergic and some noncholinergic neurons

1. This enzyme is not a good marker for cholinergic synapses 

(ChAT is)

iii. Nerve gas and some insecticides block AChE

1. Inhibition of AChE prevents the breakdown of ACh

6. Catecholaminergic neurons

a. Catecholamine neurotransmitters all have tyrosine as a precursor i. Dopamine (DA)

ii. Norepinephrine (NE)

iii. Epinephrine (adrenaline)

b. Involved in mood, movement, attention, and autonomic functions

7

c. All contain tyrosine hydroxylase (TH), catalyzes the first step; converts  tyrosine into dopa

i. Good marker for tracking catecholaminergic neurons

ii. Rate limiting step

iii. Uses end­product inhibition

1. Increased catecholamine build up in cytosol inhibits TH

iv. Increased Ca2+ in the presynaptic cell increases TH activity 

(because a lot of catecholamines have been released)

8

d. Dopaminergic neurons

i. Dopa is converted into dopamine by dopa decarboxylase

1. Dopa decarboxylase is abundant; amount of dopamine 

synthesized depends on the amount of dopa available

ii. Parkinson’s disease: dopaminergic neurons degrade and die

1. Treatment: administer dopa to increase the amount of 

dopamine available for release 

a. Can’t administer dopamine because it cannot cross 

the blood­brain barrier

e. Norepinephrine (NE) neurons

i. Norepinephrine neurons contain dopamine B­hydroxylase (DBH) which converts dopamine to norepinephrine

1. DBH is found in synaptic vesicles; in noradrenergic axon 

terminals, dopamine is transported from the cytosol to the 

synaptic vesicles to be made into norepinephrine

ii. Norepinephrine has the most diffuse distribution

iii. Activated by new, non­painful stimuli

iv. Modulate attention, feeding behaviour, sleep, mood, arousal, 

learning, memory, pain, brain metabolism

v. Neurons are in the locus coeruleus and project to cortex, 

hypothalamus and hippocampus

f. Epinephrine (adrenaline)

i. Adrenergic neurons contain phentolamine N­methyl transferase  (PNMT)

1. PNMT is found in the cytosol

2. Norepinephrine must be made in a vesicle and then 

released into the cytosol to be made into epinephrine

3. Epinephrine is transported back into vesicle for release

ii. Epinephrine also acts as a hormone when released into the 

bloodstream by the adrenal glands

iii. Major groups of neurons are found in the medulla

iv. Present at lower levels than other catecholamines

v. Present in fewer neurons, function in CNS is not known

g. Catecholaminergic neurons

i. Are not degraded in the synaptic cleft

ii. They are transported back into the presynaptic neuron by specific  Na+ dependent transporters

1. Amphetamines and cocaine block the reuptake increasing 

the binding of neurotransmitters with post synaptic 

receptors

iii. After reuptake catecholamines can be:

1. Reloaded back into vesicles

9

iv. Destroyed by monoamine oxidase (MAO) in the outer­membrane  of the mitochondria 

v. Antibodies to enzymes in the pathways are used to identify 

catecholaminergic neurons

10

7. Serotonergic neurons

a. The amine neurotransmitter serotonin is also called 5­hydroxytryptamine (5­HT)

b. It is derived from the amino acid tryptophan

i. Tryptophan comes into the body through diet and is carried into  the brain by the blood

c. Serotonergic neurons are few in number but have a widespread  distribution and are therefore widespread in function

i. Controls mood, emotional behaviour, and sleep

ii. Neurons are found in the pons and the upper brainstem

iii. Projections are to the forebrain

iv. Raphe nucleus neurons regulate pain signaling

d. Serotonin is a precursor to melatonin in the pineal gland

e. Synthesis:

i. Tryptophan is converted to 5­hydroxytryptophan (5­HTP)

intermediate by the enzyme tryptophan hydroxylase

ii. 5­HTP is then converted to 5­HT (serotonin) by the enzyme 5­

HTP decarboxylase 

iii. Synthesis is limited by the amount of tryptophan in extracellular  fluids

f. Serotonin reuptakes by a specific transporter

i. Antidepressants (Prozac) and antianxiety drugs inhibit serotonin  reuptake causing an increase in 5­HT receptors

ii. Ecstasy on the other hand, stimulates serotonin release to produce  sensory enhancement and empathy

1. Long term use may destroy serotonergic projections

2. Short term use may produce tachycardia, hyperthermia, and

dehydration

g. After reuptake serotonin is: 

i. Repackaged into vesicles for reuse

11

ii. Degraded by MAO

12

8. Amino acid neurotransmitters

a. Glutamate (Glu), Glycine (Gly), Gamma­amino­butyric acid (GABA)  b. Glutamate and glycine are amino acids used to make proteins

i. They are synthesized from glucose

ii. They are found in every cell but glutamatergic cells have a higher  concentration of them (2­3x higher)

c. Glutamate: the major excitatory neurotransmitter (half of all synapses in  the brain)

i. Involved in learning, memory, and motor functions

ii. Implicated in ALS, long term depression, long term potentiation iii. Excitotoxicity (nerve cells are killed by excessive stimulation) by  glutamate during a stroke may play a role in Alzheimer’s 

iv. Glutamate is taken up by glial cells and recycled

1. Glial cells turn glutamate back into glutamine

2. The neuron reuptakes glutamine and converts it to 

glutamate again 

d. GABA is synthesized by neurons that use it as a neurotransmitter i. GABA: major synaptic inhibitor

ii. GABAergic neurons are distributed widely

1. Mostly present as interneurons; can be in purkinje cells: 

projection neurons (not in peripherals)

iii. Glutamate is made into GABA by an enzyme, glutamic acid 

decarboxylase (GAD)

1. GAD is a good marker for GABAergic neurons

2. GAD is not present in glutamatergic neurons or glia

iv. GABA is packaged into synaptic vesicles by a vesicular 

inhibitory amino acid transporter (VIATT)

v. Metabolized by transporters (GATs) into neurons and glia

1. Broken down into the mitochondria

vi. GABA signaling deficits: Huntington’s, Parkinson’s, 

schizophrenia

vii. Barbiturates: alter GABA receptors (used to treat epilepsy)

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e. Glycine: inhibitory neurotransmitter 

i. GABA concentrated in the CNS cortex; glycine is everywhere

1. Half of inhibitory synapses in the spinal cord

ii. Synthesized from serine by serine hydroxymethyltransferase iii. Loaded into vesicles by a vesicular inhibitory amino acid 

transporter

iv. Removed from cleft by plasma membrane glycine transporters 9. ATP: an excitatory neurotransmitter 

a. Usually packed in vesicles with other neurotransmitters (co­transmitter)  b. ATP and adenosine receptors are widespread

c. ATP binds to purinergic receptors

i. Ligand gated (G­protein coupled) receptors and transmitter gated 10. Endocannabinoids: neurotransmitters that use retrograde signaling: communication from post synaptic neurons to presynaptic terminals a. Inhibit presynaptic Ca2+ channels to prevent release of neurotransmitters i. Firing of action potentials on postsynaptic neurons cause voltage  gated calcium channels to open

ii. Calcium enters the cell and stimulates the synthesis of 

endocannabinoids from lipids

b. Endocannabinoids are not packaged in vesicles; made rapidly on demand i. They are small and membrane permeable

c. Bind to CB1 receptors (G­protein coupled) on presynaptic terminals 11. Nitric oxide (NO)

a. Synthesized from amino acid arginine

b. Released by postsynaptic neurons (retrograde signaling)

c. Permeable to membranes

d. Regulates blood flow when not being used as a neurotransmitter

14

12. Transmitter­gated channels

a. Structure

i. Most transmitter­gated channels have a structure similar to 

nicotinic acetylcholine receptors (nAChR) from skeletal muscles

ii. Contain 5 subunits made up of the four possible types:  ,  ,  ,  α β γ δ iii. ACh binding sites require   subunit, where the ACh binding sites  α are

1. It requires two ACh molecules to bind to the two    α

subunits in order to open the channel

iv. Each of the 5 subunits is made up of 4 alpha helical trans

membrane regions

v. Glutamate receptors are an exception: made from four subunits  that do not span the membrane

vi. There are unique differences that account for ligand binding, Na,  K, Ca, Cl, etc. permeability

b. Amino acid gated channels

i. Amino acid­gated channels mediate most of the fast synaptic 

transmissions in the CNS

ii. Involved in many sensory systems, memory and diseases

iii. The pharmacology of their binding sites describes which 

transmitters affect them and how drugs interact with them

iv. The kinetics of transmitter binding and channel gating determine  the duration of their effects

v. The selectivity of the ion channels determines whether they 

produce excitation or inhibition, and whether calcium enters the 

cell in significant amounts

15

vi. The conductance of open channels helps determine the magnitude  of their effects

16

vii. Glutamate­gated channels: there are three types

1. AMPA: permeable to Na+ and K+ 

a. Mediate excitatory transmissions

b. Activation causes depolarization because Na+ entry 

is more than K+ exiting

c. These coexist with NMDA receptors

2. NMDA: permeable to Ca+, Na+ and K+ 

a. Inward current is voltage­dependent: the channel 

will open when the cell is depolarized (by AMPA)

b. When the channels open, Ca+ and Na+ enter the cell 

and K+ leaves

3. Kainate

viii. GABA­gated channels

1. GABA is responsible for inhibition in the CNS; glycine 

mediates everywhere

2. GABAA, GABAB, GABAC

a. A and C are ionotropic: inhibitory; gate Cl 

b. B is metabotropic

3. GABAA and glycine receptors open a gate for Cl 

a. Their structures are similar to nAChR 

b. α β  binding subunits,   nonbinding

4. GABAA receptors have several sites where chemicals can 

modulate its function 

a. Benzodiazepines increase frequency of opening

b. Barbituates increase the time the channel is open 

ix. Glycine­gated channels

1. Ligand gated Cl­ channels 

2. Similar in structure to GABAA receptors

3. Cys­loop family member

4. Strychnine is an antagonist 

17

13. G­protein coupled receptors

a. Transmission at G­protein coupled receptors requires 3 steps: i. Neurotransmitter binds to the receptor protein

ii. G­protein is activated

iii. The effector systems are activated

b. Structure of G­coupled protein receptors

i. Consist of one polypeptide with 7 transmembrane alpha helices ii. 2 of the extracellular loops form binding sites for the ligands 1. G proteins bind to some of the intracellular loops 

iii. 100 different G protein linked receptors are known

iv. Structural variations determine which G­proteins and which  effector systems are activated in response to transmitter binding

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c. G proteins: guanosine triphosphate (GTP) binding proteins

i. There are about 20 different kinds of G proteins

ii. Three subunits:  ,  ,  α β γ

iii. Basic mode of operation:

1. When inactive, the   subunit of the G protein binds GDP α

2. When activated by a G protein coupled receptor, the GDP 

is exchanged for GTP 

3. The activated G protein splits into Gα and Gβγ and they 

both activate effector proteins

4. The Gα subunit slowly removes one phosphate from GTP 

converting it back to GDP to terminate the cycle

iv. Gs is stimulatory, Gi is inhibitory (can close and open channels) d. Shortcut pathway: fastest g protein coupled system (30­100 msec) i. G protein binds to ion channels causing them to open or close

ii. Process is localized: the G protein does not move far

e. Second messenger cascades: requires multiple steps

i. G protein activates enzyme which activates downstream enzymes ii. Kinases and phosphates are involved in many cascades

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f.  Activated G proteins can sometimes stimulate multiple pathways g. Different G proteins can have opposite effects

i. Processes are regulated by stimulation (Gs) and inhibition (Gi)

h. Signal cascades

i. Slow process but has its advantages

ii. Amplification: the amplification of one g protein coupled receptor can lead to the activation of many ion channels

1. A neurotransmitter can bind to one receptor and activate 

many g proteins

iii. Provide many sites for further regulation

iv. Longer range of signaling: cascades; cascades can then interact  with other cascades

v. Long lasting effects: memories

vi. Kinases and phosphates are involved in many cascades

14. Divergence and convergence in neurotransmitter system

a. Divergence: the ability of one transmitter to activate more than one  subtype of receptor and cause more than one type of postsynaptic response

b. Convergence: multiple transmitters each activating their own receptor  type converge to influence the same effector system

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Chapter 7: The Structures Of The Nervous System Victoria Gonzalez  

Learning Objectives:

∙ Understand basic anatomical terms

∙ Know basic brain anatomy

∙ Understand imaging techniques used in neuroscience ∙ Understand basic elements of embryonic development of the  nervous system

∙ Know the structure and function of divisions of the CNS  (telencephalon, diencephalon, etc.)

1. Anatomical terms (humans)

a. Anterior/rostral: towards forehead

b. Posterior/caudal: towards the back

c. Dorsal: top of head  

d. Ventral: towards belly (front)

e. Midline: line running down the middle of the nervous  system

f. Medial: towards the midline

g. Lateral: away from the midline

h. Ipsilateral: same side

i. Contralateral: opposite sides

2. Planes of section

a. Sagittal plane: splits the brain into equal left and right  halves

b. Horizontal/transverse plane: cut is parallel to the  ground; divides the brain into dorsal and ventral parts

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c. Coronal plane: perpendicular to the ground (and to  sagittal plane); splits brain into anterior and posterior parts

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3. The central nervous system: brain and spinal cord

a. Brain consists of the cerebrum, the cerebellum, and the  spinal cord

i. Cerebrum: cortex of the brain

1. Has two hemispheres working  

contralaterally: right side of cerebrum  

receives input from left side of body

ii. Cerebellum: controls movement

1. Contains as many neurons as the cerebrum

2. Has many connections to cerebrum and spinal  

cord

3. Functions ipsilaterally: right side of  

cerebellum controls right side of body

iii. Brain stem: regulates body temperature, breathing, and consciousness

1. Most primitive part, but essential for life

2. A relay center that connects the spine and  

brain

b. Spinal cord: encased in the vertebral column

i. Spinal nerves are part of the peripheral nervous  

system (PNS)

ii. Spinal nerves attach to spinal cord by two branches:

1. Dorsal root: sensory neurons

a. Afferent: carry information to the CNS

2. Ventral root: motor neurons

a. Efferent: carry information away from  

CNS

4. Peripheral nervous system

a. Somatic (voluntary)

i. Spinal nerves that innervate muscles, skin, and joints ii. Soma (cell bodies) are in CNS, axons are in PNS

iii. Sensory neurons enter spine by dorsal roots; cell  

bodies are located in the dorsal root ganglia

b. Visceral (involuntary)

i. Also called autonomic nervous system (ANS)

ii. Controls sensory and motor (smooth muscle)  

functions

iii. Organs, glands, blood vessels

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5. Cranial nerves

a. 12 pairs; numbered by Galen anterior to posterior

b. Exit the brain stem and innervate the head

c. Some are part of CNS, some are part of PNS (both somatic  & visceral)

6. Meninges: three layers that cover and protect the CNS a. Dura mater: outermost layer

i. Forms a hard, inelastic layer around the brain and  

spinal cord

b. Arachnoid membrane: look and consistency of a spider  web

i. Subarachnoid space: filled with cerebrospinal fluid  (CSF)

c. Pia mater: thin membrane that adheres close to the brain i. Blood vessels run along the pia mater

7. Ventricular system

a. The brain has 4 ventricles filled with CSF

b. CSF is produced in the choroid plexus (on the walls of the ventricles)

c. CSF circulates to the subarachnoid space (between  arachnoid and pia)

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d. CSF is absorbed into the bloodstream via the arachnoid  villi

e. Hydrocephalus: excess CSF build up in ventricles i. Sometimes babies are born with this; since their skull is soft, their head expands and does not cause brain  

damage

ii. In adults, skull is hard and cannot expand causing  intra cranial pressure and brain damage or death

iii. Treatment involves draining the ventricles

8. Brain imaging techniques

a. Computed Tomography (CT scan): x-rays with a large  amount of computer analysis to construct a 3D image of a  slice of the brain

b. Magnetic Resonance Imaging (MRI): excite protons to  high energy state with electromagnetic waves and  

measure the frequencies emitted; frequency is proportional to the size of the field

i. Replaced MRI; more detailed image without x

irradiation  

ii. Makes a detailed image of the whole brain; any  

orientation

iii. Protons are spinning a specific tilt normally, when  disrupted by magnetic fields they change the spin  

and tilt, when they return to their original state they  

produce radio signals detected by the MRI machine,  

images are made

c. Diffusion tensor imaging (DTI): enables visualization of  large bundles of axons in the brain by measuring water  diffusion

d. Functional brain imaging: measures blood flow and  metabolism; neurons that are active demand more glucose and oxygen

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i. Positron Emission Tomography (PET scan): uses  a positron emitting isotope that is taken up by cells

ii. Functional MRI (fMRI): observes the  

oxyhemoglobin to deoxyhemoglobin ratio

1. Has a better resolution and is faster than PET

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9. Formation of the neural tube from an embryo

a. Gastrulation: single layered blastula is reorganized into a  flat disk with three layers:

i. Endoderm: gives rise to internal organs (inside)

ii. Mesoderm: gives rise to muscle and skeleton  

(middle)

iii. Ectoderm: gives rise to the nervous system and skin (outside)

b. Neurulation: transformation of the neural plate into the  neural tube

i. Neural plate: part of the ectoderm that gives rise to the nervous system

ii. After 3 weeks of gestation (pregnancy), a neural  

groove forms in the neural plate running rostral to  

caudal

iii. Walls of the groove (neural folds) fuse to form a  

neural tube

1. At embryonic day 22

2. The CNS is derived from the walls of the neural  

tube

iv. Part of the ectoderm pinches off to the sides of the  neural tube and becomes the neural crest

1. PNS cells come from the neural crest

v. The mesoderm forms bulges on the sides of the  

neural tube called somites

1. Somites for 33 vertebra and associated skeletal

muscles

vi. Defects in neurulation:  

1. Failure of the neural tube to close can cause  

birth defects (1 out of 500 births)

2. Anencephaly: skull and forebrain degenerate  

because anterior neural tube doesn’t close  

(fatal)

3. Spina bifida: posterior neural tube doesn’t  

close (usually not fatal)

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10. Differentiation: the process by which structures become  more complex and functionally specialized during development a. 3 primary vesicles form at the rostral end of the neural  tube: the brain is derived from these

i. Prosencephalon (forebrain): rostral-most vesicle ii. Mesencephalon (midbrain)

iii. Rhombencephalon (hindbrain): connects with the caudal neural tube to give rise to the spinal cord

11. Forebrain differentiation

a. Secondary vesicles sprout from prosencephalon

i. Optic vesicles: form the optic nerves

1. Grow and invaginate to form the optic stalks  

and the optic stalks

2. Become optic nerves and retina

3. The retinas and optic nerves are part of the  

brain, not the PNS

ii. Telencephalic vesicles: cerebral hemispheres

1. Telencephalon: the telecephalic vesicles

2. The telencephalic vesicles grow and envelop  

the diencephalon

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3. Olfactory bulbs arise from telencephalon

4. The cells of the telencephalon walls divide,  

differentiate, and become several different  

structures

5. White matter develops carrying axons to and  

from neurons of the diencephalon

b. Diencephalon: the central structure that remains after  the secondary vesicles have sprouted off

c. Ventral-medial surfaces of the hemispheres fuse with the  lateral surfaces of the diencephalon

d. Ventricles

i. Lateral ventricles: in the telencephalon

ii. Third ventricle: in the diencephalon

e. Telencephalon forms cerebral cortex and basal cortex f. Diencephalon becomes thalamus and hypothalamus g. Forebrain neurons extend axons in 3 major systems:

i. Cortical white matter: contains axons that run to  and from neurons in the cerebral cortex

ii. Corpus callosum: forms an axonal bridge that  

connects the two hemispheres

iii. Internal capsule: links the cortex with the thalamus iv. Tract: axons with the same origin and destination

v. Bundle: axons that run together but do not have the  same origin or destination  

12. Forebrain structure-function

a. The forebrain is responsible for many higher functions:  cognition, perception, voluntary action

b. Most important part of the forebrain: cerebral cortex c. The thalamus is an important relay center of senses i. Thalamic neurons send axons to cortex via internal  capsules

ii. Axons of internal capsules carry information to the  cortex on the contralateral side of the body

1. Sensory on right side of the body; left thalamus

responds; left internal capsule relays  

information to left side of the brain

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d. The cortex communicated with the brainstem via internal  capsules

i. Some connections extend past the brainstem to the  spinal cord

e. Basal ganglia in the basal telencephalon; controls  movement

f. Hypothalamus: controls many “old” and basic functions,  ANS (involuntary nervous system), controls hormones in  the pituitary, regulates body temperature

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13. Midbrain differentiation

a. The midbrain does not change a lot after the neural tube is  formed

b. The dorsal (top) surface of the mesencephalon becomes  the tectum

c. The bottom of the midbrain becomes the tegmentum i. Cerebral aqueduct forms in the middle of the  

tegmentum

1. Good landmark for identifying the midbrain

14. Midbrain structure-function

a. Midbrain serves as a pathway for information between the  forebrain and the spinal cord

b. Midbrain is involved in sensory systems and movement  c. The tectum differentiates into two structures:  

i. Superior colliculus (optic tectum): receives input  from the eye and controls eye movements

ii. Inferior colliculus: relays information from ears to  thalamus

d. Tegmentum: controls movement, pain, pleasure, mood,  consciousness

15. Differentiation of the hindbrain

a. Metencephalon: rostral hindbrain; becomes cerebellum and pons

b. Myelencephalon: caudal hindbrain; becomes medulla oblongata

c. Fourth ventricle forms; continuous with the cerebral  aqueduct of the midbrain

d. Medullary pyramids form: bundles of axons in a  

triangular shape connected to the spinal cord

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16. Hindbrain structure-function

a. Hindbrain is a relay center between forebrain and spinal  cord

b. Cerebellum: receives a large input from the spinal cord  and pons

i. Responsible for coordinated movements

c. Pons: 90% of descending axons passing through the  midbrain synapse here

i. Major switchboard connecting the cortex to the  

cerebellum

d. Medulla: involved in sensory (auditory, taste, touch) and  motor functions (tongue movements)

e. Medullary pyramids: axons that bypass the pons enter  here

i. Axon bundles running through the medullary  

pyramids make up the corticospinal tract

f. Pyramidal decussation: near where the medulla joins  the spinal cord, pyramidal tracts cross from one side to the  other

i. Explains contralateral processing

17. Differentiation of the spinal cord

a. Gray matter (neurons):

i. Dorsal horn: upper part of “butterfly”

ii. Intermediate zone

iii. Ventral horn: lower part of “butterfly”

b. White matter (axons):

i. Dorsal column

ii. Lateral column

iii. Ventral column

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18. Spinal cord structure-function

a. Grey matter:

i. Dorsal horn: receives sensory input from dorsal root (afferent)

ii. Ventral horn: projects to ventral roots onto muscles (efferent)

iii. Intermediate zone: interneurons, coordinate  

sensory and brain information to form output

b. White matter:

i. Dorsal columns: carry sensory information to  

medulla (ipsilaterally)

1. Neurons in the medulla cross and connect to  

thalamus on contralateral side

ii. Lateral columns: axons from descending  

corticospinal tract which crossed at pyramidal  

decussation; they innervate the intermediate zone  

(interneurons) and the ventral horn which controls  

voluntary movement

c. Most tracts in the spinal cord are one-way

19. Genesis of neurons in 3 stages: proliferation, migration,  and differentiation

a. Cell proliferation

i. Early in development the ventricle walls are made of  2 layers:

1. Ventricular zone: lines the inside of each  

vesicle

2. Marginal zone: on the outside facing the pia  

mater

ii. Process:

1. A cell in the ventricular zone extends a process

that reaches upwards towards the pia mater

2. The nucleus of the cell migrates upward from  

the ventricular surface toward the pial surface

3. The cell’s DNA is copied

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4. The nucleus, containing two complete copies of

the genome, settles back to the ventricular  

surface

5. The cell retracts its arm from the pial surface

6. The cell divides in two

iii. Radial glial cells: the dividing cells; they give rise  to all neurons and astrocytes of the cerebral cortex

1. Multipotent stem cells: assume different  

destinies

iv. Neocortical neurons are mostly made before birth,  but a small amount is still made in adult life (only in  

a small part of brain)

b. Determination of cell fate

i. The fate of the daughter cell is determined by:  

1. Age of precursor cell

2. Position within ventricular zone

3. Environment at the time of division

ii. Proliferation of pyramidal neurons and astrocytes: in  the ventricular zone of the telencephalon

iii. Inhibitory interneurons (GABA) and oligodendrocytes  are generated in the ventricular zone of the ventral  

telencephalon; cells must migrate laterally

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20. Development of cortex

a. Neuronal cells differentiate first

b. Astrocyte differentiation

c. Oligodendrocytes differentiate last

21. Rat brain vs. human brain

a. Similarities

i. Telencephalon is rostral (front) to diencephalon

ii. Diencephalon surrounds the third ventricle

iii. Midbrain surrounds the cerebral aqueduct

iv. Fourth ventricle is surrounded by the pons, medulla,  and cerebellum

b. Differences

i. Sulci (grooves) and gyri (bumps)

ii. Surface area

iii. Human olfactory bulb is small

22. Three types of cortex:

a. Hippocampus: only one layer; is medial to lateral  ventricles

i. For learning and memory

b. Olfactory cortex: two cell layers; posterior to olfactory  bulb

c. Neocortex (cortex): only in mammals; “new” part of  cerebral cortex

i. Responsible for voluntary movement, vision, hearing, and somatic sensation

23. Cerebral cortex

a. Systems for learning, speech, sensations, cognition,  perceptions, voluntary movement

37

b. Neuronal cell bodies are arranged in layers

c. The most superficial layer has no neurons (layer 1,  molecular layer)

i. Pyramidal cells extend to layer 1

d. Areas of neocortex

i. Brodmann made a cytoarchitectural map where  

areas with a common structure were given a number

1. Thought that different areas had different  

functions but never proved it

2. Some of his predictions were right: 17 is vision,

4 is motor

ii. Types of cortex:

1. Primary sensory

2. Secondary sensory

3. Motor

4. Association areas: in temporal and frontal lobes

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Chapter 8: Chemical Senses

Victoria Gonzalez

Learning objectives

∙ Understand basic anatomy of taste receptors

∙ Know basic signal transduction mechanisms for each taste ∙ Know basic anatomy of olfactory receptors

∙ Understand olfactory signal transduction

∙ Understand chemical sensory pathways to the brain

1. Introduction

a. Of all sensory systems, chemical sensation is the oldest  and most pervasive across species; universal

b. Taste (gustation) and smell (olfaction): both work  together for flavor to detect the environment

i. Signals are integrated in the orbitofrontal area

c. Chemoreceptors: monitor internal environment, chemical communication, and integration

d. Senses are important for hunger, emotion, sex, and  memory

2. Taste

a. Taste is needed to determine what is food from what is  poison

b. Enjoy sweet, not bitter things  

i. The threshold for salty and sweet is high

ii. The threshold for bitter is low

c. We crave nutrients that are lacking

d. Only 5 basic tastes: sweet, salty, bitter, sour, umami i. Acids are usually sour

ii. Salts are usually salty

iii. Different structures are sweet: aspartame made of  amino acids is sweeter than sucrose (table sugar)  

iv. Magnesium, potassium, and caffeine are bitter

v. Smell, combinations of receptors, pain, texture,  

visual cues, and temperature all contribute to flavour

e. Organs of taste

i. We taste with our tongue, palate, pharynx, and  

epiglottis

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ii. Taste buds are scattered on the sides of the tongue  so that all parts with taste buds are sensitive to all  

basic tastes

1. Taste bunds are located on papillae: bumps on

tongue

2. Each papillae has from 1 to hundreds of taste  

buds

3. Each taste bud has 50 to 150 taste bud cells

4. Taste buds account for only 1% of tongue  

epithelium  

5. People have between 500 and 20,000 taste  

buds

iii. Taste bud cells are sometimes specific to taste,  

sometimes not

iv. The sensory part of taste receptor cell is at the apical end

v. These microvilli stick out into the taste pore and are  exposed to tastants in the mouth

vi. Taste cells are replaced every two weeks

vii. Taste receptor cells are not genuine neurons

viii. Types of taste bud cells:

1. Type I: Na+ sensing; like glial cells

2. Type II: known as receptor cells; use G protein

coupled receptors

40

a. Detect either bitter, sweet, or umami  

(only one)

b. Have no synapse

3. Type III: known as presynaptic cells; form  

synapses, vesicles, use voltage gated calcium  

channels (VGCC)

a. Respond to sour taste

4. Type IV: known as basal cells; progenitors of  

other taste sensing cells

f. Response of taste cells

i. When exposed to chemicals, taste cells generate  

receptor potentials and the cell depolarizes

ii. Sour and salty release serotonin

iii. Sweet, umami, and bitter release ATP

iv. Most cells respond strongly to one taste

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g. Mechanisms of taste transduction

i. Transduction: an environmental stimulus causes an electrical response in a sensory receptor cell

ii. Each basic taste uses one mechanism; not all  

understood

iii. Many animals are used for studies

iv. Salty and sour: pass through ion channels

v. Sour: bind to block ion channels

vi. Bitter sweet umami: use G-protein-coupled receptors h. Saltiness

i. Sodium ions enter through amiloride-sensitive  

sodium channels

1. Open all the time, depolarizes the taste cell  

when sodium enters in the cell; insensitive to  

voltage

ii. Type I cells involved

iii. Anions affect the taste of salts

i. Sourness

i. Low pH (acids)

ii. Type III presynaptic cells

iii. Acids dissolve in water and produce H+ 

iv. Protons enter proton sensitive TRP (transient  

receptor potential) channels

v. Bind to block K+ selective channels to cause  

depolarization

vi. Selectively expressed in a unique population of taste  bud cells

vii. May also be used to detect pH in spinal cord

j. Bitterness

i. Use Type II cells (no synapse)

ii. Two families of taste receptor genes: T1R and T2R

1. They are G-protein coupled  

2. Dimers: two T2R proteins bound to each other

iii. Many poisons are bitter so there are many genes  

used to recognize bitter (at least 30 T2R)

1. Multiple T2R genes in each taste cell

iv. Some taste cells only express bitter receptors, some  communication to specific gustatory axons

v. When a tastant binds to a bitter receptor, it activates a G protein, which stimulates the enzyme PLC

vi. PLC and taste cell specific cationic channel

k. Sweetness

i. Use Type II cells (no synapse)

ii. There are many different sweet tastants but are all  detected by the same receptor

1. Dimer T1R2+T1R3

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iii. Same second messenger system as bitter

iv. Sweet receptors are expressed in specific cells  

connected to the sweet gustatory axons

l. Umami (amino acids)

i. Use Type II cells (no synapse)

ii. All detected by the same receptor

1. Dimer T1R1+T1R3

2. T1R3 is in sweet too

3. T1R1 is what determines umami

iii. Activate the same second messenger system as for  bitter

iv. Umami receptors connect to specific gustatory axons m. Central taste pathways

i. Flow of taste information: taste buds, primary  

gustatory axons, brain stem (medulla), thalamus,  

cortex (ipsilateral flow)

ii. Gustatory axons carried by:  

1. Cranial nerve VII (facial)

2. Cranial nerve IX (glossopharyngeal)

3. Cranial nerve X (vagus)

iii. Cranial nerves synapse in the gustatory nucleus in  the medulla

iv. Neurons of the gustatory nucleus synapse on the  

ventral posterior medial (VPM) nucleus in the  

thalamus

v. Axons are then sent to the primary gustatory  

cortex

1. Located on Brodmann’s area 36 of the cortex

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vi. Ageusia: a loss of taste perception

1. Caused by lesions to VPM, thalamus, or  

gustatory cortex

vii. Gustation is important for vomiting, swallowing,  

digestion, breathing

viii. Gustatory information is distributed to the  

hypothalamus and the medulla

n. Neural coding of taste

i. Some afferent neurons are tightly tuned (specific),  

others are broadly tuned (not specific)

ii. Afferent neurons show response profiles similar to  narrowly tuned taste bud receptor cells and broadly  

tuned presynaptic cells (but this is not clear yet)

iii. Gustatory nucleus axons are broadly tuned all the  way to the cortex

iv. Are there more tastes? Perhaps fats

1. Fatty acids are potent stimuli

2. There are membrane receptors for fatty acids  

on taste bud cells

3. Smell (olfaction)

a. We can smell 100,000s of different substances; most are  unpleasant

b. Other animals use pheromones to communicate

i. Detected by vomeronasal organ (vestigial in  

humans)

c. Olfactory organs

i. We do not smell with our nose, we smell with the  

olfactory epithelium: thin sheet of cells high up in  

the nasal cavity

ii. Olfactory epithelium has three cell types:

1. Olfactory receptor cells: sites of  

transduction

a. Genuine neurons

b. Have a 4-8 week life cycle

2. Supporting cells: similar to glia

a. Produce mucus

3. Basal cells: source of new receptor cells

iii. Odorants dissolve in mucus

1. Mucus: mixture of antibodies, proteins, and  

odorant binding proteins which concentrate  

odorants

iv. Sensitivity to smell is dependent on the size of the  olfactory epithelium and the number of receptors

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1. Dogs have more receptors and a larger  

epithelium surface area

v. Olfactory Receptor neurons

1. Have only one dendrite

2. Have an unmyelinated axon

3. Axons from olfactory nerve make up cranial  

nerve I

4. Cranial nerve I connects to the olfactory bulb

5. Axons are fragile and can be easily damaged  

producing anosmia: inability to smell

d. Olfactory signal transduction

i. Olfactory receptor neurons have a single dendrite  

that ends with a small knob on the surface of the  

epithelium; on the knob are cilia in the mucus  

ii. Odorants dissolve in the mucus and bind to the cilia  to activate the transduction process by G proteins  

(Golf)

iii. Golf activates adenylyl cyclase  

iv. Adenylyl cylase forms cAMP

v. cAMP binds to a cation channel

vi. Cation channel opens and there is an influx of Na+ and Ca2+ 

vii. Ca2+ opens Cl- channels; Cl- leaves the cell

viii. Depolarization (receptor potential) occurs and an  action potential occurs if the threshold is reached

ix. Signal fades quickly

1. Adaptation: decreased response despite the  

continuing presence of a stimulus

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e. Olfactory receptor genes

i. There are many different types of odorant receptor  proteins: each cell expresses only one type

ii. The different receptor proteins are organized into  

zones

iii. Vomeronasal organ expresses its own receptors; few  functional proteins

iv. Olfactory receptor proteins are G-protein coupled

1. Have 7 transmembrane proteins

v. All receptors are linked to Golf

vi. cAMP is the second messenger

vii. Population coding (combination of responses from  many cells) influences transduction

1. Receptors are broadly tuned

2. The amount of odorant influences response

f. Central olfactory pathways

i. Olfactory receptor neurons synapse on the  

glomeruli in the olfactory bulbs

1. Each glomerulus receives input from a broad  

area of olfactory epithelium

2. Each glomerulus receives input only from  

receptor cells expressing the same gene

3. The array of glomeruli is a map of genes (map  

of odor information)

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4. Temporal patterns of neuron firing may  

represent odor qualities

ii. Glomeruli and bulbs communicate to modify the  

input to brain

iii. Higher brain areas also connect to bulbs

iv. Olfactory tracts connect to cortex before the  

thalamus

1. Different than for other systems

v. Olfactory connections to forebrain areas are involved  in memory, motivation, and emotion

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