Test Two Study Guide
Test Two Study Guide NEUROSC 3000 - 020
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NEUROSC 3000 - 020
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This 46 page Study Guide was uploaded by Victoria Gonzalez on Wednesday November 4, 2015. The Study Guide belongs to NEUROSC 3000 - 020 at Ohio State University taught by Robert Boyd in Summer 2015. Since its upload, it has received 36 views. For similar materials see Introduction to Neuroscience in Neuroscience at Ohio State University.
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1 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 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 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 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 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 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 + 2+ K and Ca + 1. High K concentration causes depolarization (action potential) and stimulates release 2. High Ca concentrations expel neurotransmitters from presynaptic axons v. Optogenetics: used to control signaling in individual neurons 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 5 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 in+reasingcholine 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 6 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. Increa2+d catecholamine build up in cytosol inhibits TH iv. Increased Ca 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) 13 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 Ca 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 α subunit, where the ACh binding sites 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. GABA , GABA , GABAB C a. A and C are ionotropic: inhibitory; gate Cl b. B is metabotropic 3. GABA anA glycine receptors open a gate for Cl a. Their structures are similar to nAChR b. α binding subunits, β nonbinding 4. GABA reAeptors 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 GABA reAeptors 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 18 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 α subunit of the G protein binds GDP 2. When activated by a G protein coupled receptor, the GDP is exchanged for GTP 3. The activated G protein splits into G αnd G aβγ they both activate effector proteins 4. The G subunit slowly removes one phosphate from GTP α converting it back to GDP to terminate the cycle iv. G sis stimulatory, G i 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 19 20 f. Activated G proteins can sometimes stimulate multiple pathways g. Different G proteins can have opposite effects i. Processes are regulated by stimulation (G ) snd inhibition (G) i 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 21 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 22 c. Coronal plane: perpendicular to the ground (and to sagittal plane); splits brain into anterior and posterior parts 23 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 24 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) 25 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 26 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 27 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) 28 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 29 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 30 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 31 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 32 33 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 34 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 35 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 36 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 38 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 39 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 41 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 42 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 43 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 44 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 (G olf iii. G activates adenylyl cyclase olf iv. Adenylyl cylase forms cAMP v. cAMP b
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