Exam 3 Bundle
Popular in Cellular Neuroscience
Popular in Neuroscience
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This 42 page Bundle was uploaded by Emma Notetaker on Wednesday November 4, 2015. The Bundle belongs to NSCI 3310 at Tulane University taught by Jeffrey Tasker in Summer 2015. Since its upload, it has received 105 views. For similar materials see Cellular Neuroscience in Neuroscience at Tulane University.
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Date Created: 11/04/15
Sensory Systems 11/4/15 2:16 PM • 1. Somatic Sensory System (touch, heat, pain) • Proprioceptive System (self) • 2. Auditory System / Vestibular System (hearing/balance) • 3. Visual System (sight) • 4. Olfactory System (smell) • 5. Gustatory System (taste) • common organization of systems • Sensory Transduction: o Sensory receptors § Neurons in somatic sensory and olfactory systems § Epithelial cells in visual, auditory, gustatory systems • Encoding of 4 properties of sensations: o 1. Modality (quality) o 2. Intensity o 3. Duration o 4. Location • Neural Encoding: o Encoding of stimulus information into action potential discharge = Neural Code sensory modalities • 5 main modalities (qualities): vision, hearing, touch taste and smell • submodalities – different qualities within modality o eg: touch has pressure, temp, pain • specific receptors with each modality/submodality o vision – photoreceptors o audition – mechanoreceptors o somatic – mechanoreceptors, thermoreceptors, nociceptors o taste – chemoreceptors o smell – chemoreceptors o proprioception – chemoreceptors, mechanoreceptors, nociceptors • each modality associated with specific central pathways o relay through subnuclei of thalamus o terminate in specific cortical areas somatic sensory system • skin receptors • 3 modalities (touch/pressure, temperature and pain) • mechanoreceptors – touch o superficial – smaller receptive fields § Meissners and Merkel’s o deeper – larger receptive fields § Pacinian and Ruffini o 4 types § Pacinian corpuscules § ruffini’s endings § Merkel’s disks § Meissner’s corpuscules o hair follicle receptors • thermoreceptors – temp o free nerve endings • nociceptors – pain o free nerve endings intensity • threshold – minimal stimulus strength to elicit response • intensity o frequency code – s trength of stimulus encoded in frequency of AP discharge in SINGLE neurns § greater frequency – greater intensity o population code – strength of stimulus encoded in several neurons recruited in activity § greater intensity – greater number of neurons recruited § greater number of neurons – greater intensity location of stimulus • 1. receptive field of receptors o area of your skin that, when stimulated, elicits response in that neuron o primary sensory neuron responds to stimulation • 2. density of receptors – more receptors in fingers vs. arms o 2 point discrimination test – can discriminate as 2 points of smaller distance if higher density of receptors o allows for spatial resolution • receptive fields o sensory area sensed by neurons st o 1 order neurons/primary sensory neurons – receptor area § project to secondary neuron § o 2 nd order neurons - convergent signals § gets input from multiple primary sensory neurons § receptive field = sum of receptive fields of all the primary neurons sending messages to it • dermatomes: sensory areas served by each spinal nerve, dorsal root and spinal segment o cervical, thoracic, lumbar and sacral segments o each one served by spinal nerve, dorsal root and spinal segment duration • adaptation - all receptors adapt o receptor potential amplitude decreases with continued stimulation § goes up, adapts, comes back down (does not remain at peak) o slowly adapting receptors – tonic activation § adapt and form lower tonic frequency § at first higher frequency, then adapts to a lower one § tonic changes in sensory input o rapidly adapting receptors § rapidly shut off – no firing during stimulus but then comes back at the end § active only with onset and offset of stimulus § detecting of persistent and transient sensory signals touchpressure receptor properties • 1. size of receptive field (large vs small) • 2. adaptation to sensory stimulus o fast vs slow • small and fast – Meissner • small and slow – Merkels • large and fast – Pacinian • large and slow - Ruffini primary afferents • 4 types of sensory axons: o Aα - large diameter § proprioceptors in muscle § 80-120m/s o Aβ - mid diameter § mechanoreceptors in skin § 35-75 m/s o Aδ – small diameter § pain and temperature § 5-30 m/s o C – small diameter § temperature, pain and itch § very important for pain sensation § VERY slow - .5-2m/s • Myelinated - Aa, Ab, Ad • Unmyelinated – C organization of somatic sensory system • Receptors (submodalities) – o Mechanoreceptors – touch, pressure o Thermoreceptors - temperature o Nociceptors - pain • Primary sensory neurons – o 1 order neurons o Dorsal Root Ganglia o Peripheral end = receptor o Central end = axon terminal • 2 Main Somatic Sensory Pathways: o 1. Dorsal column-medial lemniscus pathway § Mechanoreceptors § 2 ndorder neurons in medulla § goes from medulla o 2. Spino-thalamic pathway § Thermoreceptors and Nociceptors § 2 ndorder neurons in dorsal horn § spinal pathway going all the way to the thalamus dorsal column medial lemniscus pathway • Touch/proprioception (mechanoreceptors) • Spinal cord – ipsilateral dorsal column • Medulla – dorsal column nuclei o ipsilateral (same side from which it entered) o Gracile nucleus o Cuneate nucleus nd • AT medulla, 2 order neuron sends its axon to the opposite side’s cortex • Medial Lemniscus – contralateral o white matter pathway o fiber tract from medulla to the thalamus • Thalamus – contralateral o Ventral posterior nucleus o sensory relay to the cortex – thalamic neuron synapses on cortex • 1º Somatic Sensory cortex – contralateral to where the sensory stimulus was applied spinothalamic pathway • temp/pain • Spinal cord – ipsilateral dorsal horn nd o 2 order neuron IN spinal cord § this neuron crosses midline to contralateral side § axon climbs all the way to thalamus o contralateral spinothalamic tract • Thalamus – contralateral o Ventral posterior nucleus o Intralaminar nucleus • 1º Somatic Sensory cortex o contralateral somatic sensory cortex • 4 Lobes of Cortex – frontal, parietal, temporal, occipital • Somatic sensory cortex • - Parietal lobe • - Postcentral sulcus somatic sensory cortex somatotopic organization • Complete somatotopic map of the body in somatic sensory cortex: • Disproportionate representation of parts of the body • Due to higher sensitivity (greater innervation) of parts of body and more projections to cortex from those parts of body • topographically organized = somatotopic lateral inhibition: • Center-surround receptive fields o Surround area inhibitory § allows your brain to interpret spatial environment, pinpoint where inputs are on the body o pinprick in the middle of center-surround, activates primary neuron § activates the neighboring primary sensory neurons around it (to a lesser degree) • Lateral inhibition enhances spatial resolution o Contrast enhancement nd • 2 Order Neurons – Convergence o ⇒ Projection of multiple 1 /2 st nd order cells o ⇒ Sum of receptive fields • Lateral inhibition via inhibitory interneurons – inhibition of neighbors o strong activation inhibits neighbors through interneuron o activate 2 nd order neuron BUT inhibit neighboring 2 ndorder neuron through interneuron – this allows for the point to be pinpointed, because one is being excited § inhibit the neighbors so that there is a more direct pathway, and it is more clear where the actual stimulus is located 11/4/15 2:16 PM 11/4/15 2:16 PM Synaptic Modulation 10/23/15 8:31 PM • synaptic shunting (shunting inhibition) • opening of ion channels independent of changing membrane potential • if EPSP (+ charge) goes through area of activated inhibitory (open Cl- channels), draws Cl- into cell negate that positive charge o positive charge shunted by negative charge being pulled in o negates EPSP • expressed by Ohm’s law (V=IR) • resistance decreased when chloride channels open, leads to proportionally smaller V • metabotropic receptors • G-protein coupled receptors (guanocine nucleotide binding protein) • single subunit, but can form and signal as dimers • 7 transmembrane regions • associated with G protein – GDP binding region • DO NOT form ion channels • 2nd messenger system o intracellular messenger o indirect gating of channels (targets of signal) • sequence: o receptor binding o G protein activation o 2 ndmessenger activation o kinase activation (phosphorylates target) o phosphorylation of channel protein (ion channel) • G protein activation • G protein: o 3 protein subunits (alpha, beta, gamma) § B/y form one subunit o membrane associated o GDP-bound (guanosine diphosphate) • ligand binding to GPCR o activates G protein o G protein associates with receptor o GTP (triphosphate) substitutes for GDP on alpha subunit o a subunit dissociates from B and y o a and B/y can each “signal” § ex: trigger reactions o a activates 2 nd messenger system (secondary effector) o B/y dimer can act directly on ion channels (target protein) • 2 ndmessenger systems • activation of GPRC (G protein coupled receptors) o 1. first messenger (neurotransmitter) binds to receptor o 2. G protein activated (GTP binding) § transducer (G protein) à signal transduction o 3. primary effector enzyme activated nd o 4. 2 messengers formed o 5. secondary effector enzyme activated (ex: kinase) o 6. phosphorylation • cAMP and phosphoinositol most common 2 ndmessengers • cAMP: • Gs and GI – stimulatory and inhibitory G proteins o different alpha subunits • GS: stimulates adenylyl cyclase = primary effector enzyme o adrenaline, noradrenaline, epinephrine, norepinephrine o norepinephrine activates beta receptor coupled to GS protein § when GTP added, dissociates and has a positive regulation on adenylyl cyclase (makes cAMP) § causes increase in cAMP production § increase in pKA activity • GI: inhibits adenylyl cyclase o receptor to norepinephrine and epinephrine § recruits alpha I § dissociation of alpha has inhibitory influence on adenylyl cyclase activity § down regulates – reduces cAMP production • cAMP activates cAMP-dependent protein kinase (protein-kinase A) o PKA = secondary effectory à phosphorylation of target proteins • phosphoinositol: precursor protein to UP3 and DAG • 1. G protein (GQ) – stimulates phospholipase C (PLC) o alpha Q subunit o PLC is enyme that acts on lipids • 2. phosphatifylinositol diphosphate (PIP2) – membrane lipid precursor • 3. PLC à IP3 and DAG production from PIP2 • 4. IP3 à release of calcium from intracellular stores and increases intracellular calcium concentration (can increase activity in PKC • 5. DAG à activates PKC (calcium dependent) • all of these can signal to other proteins in cell • direct actions of G proteins • via By - inhibitory • direct gating of channels WITHOUT second messenger intermediates • ex: in heart ACh muscarinic receptors (slow heart rate) • ex: GABAB receptors in brain (activated by By subunit) • GIRK channels – G protein gated inwardly rectifying potassium channels o inhibitory • GPCR can open OR close ion channels • ionotropic receptors – activation leads to opening only o local actions ONLY (ex: at synapse) – signal can trael but initlally only local • metabotropic receptors: activation can lead to both opening and closing o actions can occur distant from receptors (diffusible messengers) – not local o amplification of signals – 1 GPCR can signal to multiple G proteins, each protein can act with multiple targets § multiple signals diverge, converge at end to amplify original signal o much slower rate, longer lasting than ionotropic • prolonged opening or closing (modulates excitability of postsynaptic cell) o changes in Vm o changed is R o changes in membrane responsivity based on Ohm’s law • metabotropic receptors cause slow synaptic modulation • modulation by G protein coupled receptors • in contrast to fast excitation and inhibition by glutamate and GABA • slow modulation o slow onset and offset o slowed by intracellular signal cascade Neurotransmitter G protein-coupled receptors Glutamate mGluR 1-8 GABA GABA (B subtypes form dimers) Acetylcholine muscarinic receptors (M 1-5) Dopamine D 1-4receptors (all DA receptors) Norepinephrine/epinephrine α and β receptors (all NE receptors) Serotonin 5-HT 1,2,4-7eceptors (all except 5-HT 3 Histamine receptors H 1-4(all H receptors) Neuropeptides all neuropeptide receptors Endocannabinoids CB1 and CB2 receptors (all receptors) highlighted are GPCR • postsynaptic modulation – at dendrites or soma • axosomatic, axodendritic synapses • works via metabotropic receptors • CAN affect neuron excitability • spillover from axon into perisynaptic receptors on postsynaptic membrane o with high activity of that synapse (so much nt that it cannot be taken up completely) o increasing evidence that glia can release gliotransmitters • methods of modulation (2): o depolarization and hyperpolarization o increase/decrease in conductance/resistance (open/close channels) • ex: glutamate and GABA o glutamate à § mGluRs (metabotropic glutamate receptors)à § closing of voltage-gated channels and K leak channelsà § depolarization/excitation o GABA à § GABAB receptors (metabotropic)à § opening of K channels (GIRK - directly coupled to GABAB)à § membrane resistance decreases (more open channels) § hyperpolarization, inhibition • presynaptic modulation – at axon terminal of presynaptic neuron • due to metabotropic receptors • activation of these receptors CANNOT affect excitability of neuron– only influences neurotransmitter release at axon terminals o changes how much nt released per action potential (changes probability of release at synapse) • axo-axonic • caused by: o 1. retrograde messenger actions o 2. also caused by neurotransmitter spillage from dendrites o 3. metabotropic receptors • increases or decreases in neurotransmitter release • glutamate INHIBITORY when acting at metabotropic glutamate receptors in presynaptic terminal o different from all other glutamate receptors o mGluR receptors o act on synaptic proteins that mediate exocytosis (inhibit synaptic machinery resposible for exocytosis) § causes decrease in glutamate release § causes decrease in GABA release o each spike in graph is vesicle of glutamate release, causing inward current § mGluR agonist causes decrease in frequency of EPSC (because decrease in probability of release) § mGluR acting at glutamate synapse presynaptically to reduce frequency of vesicular release • GABA via GABAB receptors - inhibitory o modulate calcium influx – decrease/inhibit voltage-gated calcium channels – decreases exocytosis (because calcium dependent) o causes decrease in GABA release (because calcium decreased) o causes decrease in glutamate release (because calcium decreased) o outward current in graph à hyperpolarization § application of norepinephrine causes increase in frequency of those events § increases probability of release of GABA at GABA synapses (by acting at presynaptic receptors) 10/23/15 8:31 PM 10/23/15 8:31 PM Nervous System 11/4/15 2:16 PM NS = CNS + PNS • CNS: brain and spinal cord • PNS: spinal nerves, cranial nerves, ANS and SNS • afferents – sensory inputs coming IN • efferents – motor outputs going out anatomy references • human (2 axes – brain and spinal cord) o rostral (anterior, front) and caudal (posterior, back o dorsal (back) /ventral (front) o superior (top) vs. inferior (bottom/neck) • rodent (1 axis) planes of section • coronal/frontal – crown (separates front and back) • horizontal – separates top from bottom • sagittal – down the middle (splits into left and right) o midsagittal – exactly down the middle o perisagittal – off the midline neural development – neurulation (first 3 weeks) • embryo – disk made up of 3 layers o endoderm – forms viscera o mesoderm – forms bones, muscle o ectoderm – forms skin, nervous system • neurulation (first 3 weeks) o neural plate à o neural groove à § neural tube à CNS § neural crest à PNS • somites (mesoderm) – spinal cord vertebrae and somatic muscles o define different segments of vertebrae and spinal nerves differentiation – 2 phases • 1. primary vesicle formation (3 primary vesicles) o rostral end of neural tube o forms entire brain o 3 vesicles § forebrain – prosencephalon § midbrain – mesencephalon § hindbrain – rhombencephalon • 2. secondary differentiation o forebrain differentiation § secondary vesicles – paired ú 1. optic vesicles • optic stalks and cups • optic nerves • retina • part of brain ú 2. telencephalic vesicles • form cerebrum • grow and grow up over diencephalon • vesicles from ventral become olfactory bulbs • differentiation of gray matter – structures of telencephalon • differentiation of white matter formation – axonal systems, inputs and outputs § diencephalon – unpaired ú optic vesicles o telencephalon/diencephalon differentiation § gray matter (cell bodies) ú telencephalon – cerebral cortex and basal telencephalon ú diencephalon – thalamus and hypothalamus § ventricles – ú lateral ventricles (telencephalon) ú 3 rd ventricle (diencephalon) § white matter (axons connecting gray) – 3 systems ú cortical white matter – cerebral cortex ú corpus callosum – connects hemisphere ú internal capsule – cortex with diencephalon o forebrain structure – function § cerebral hemispheres ú cerebral cortex – cognition, sensory and voluntary motor control ú olfactory bulbs – olfaction relay to cortex ú basal ganglia – striatum, voluntary motor inititiation ú hippocampus – short term memory formation ú amygdala – fear and emotion § diencephalon ú thalamus – sensory relay to cortex ú hypothalamus – ANS control and endocrine system control o midbrain differentiation § tectum (ceiling)– superior colliculus, inferior colliculus § tegmentum ú substantia nigra - dopamine reward system ú motor control (Parkinson’s) ú cerebral aqueduct – connection to ventricular system o hindbrain differentiation § 3 structures: cerebellum (rostral), pons (rostral) and medulla (caudal) § rostral: ú rhombic lips swell and fuse to become cerebellum ú ventral hindbrain becomes pons § caudal – dorsal surface thins (ependymal) ú ventral becomes medulla th § 4 ventricle – CSF connected to cerebral aqueduct o hindbrain structure function § bidirectional relay between forebrain and spinal cord § cerebellum – controls movement and coordination ú convergence of inputs from spinal cord and cerebral cortex ú coordinated movements § pons – bridge to cerebellum ú 90% of descending axons from cortex synapse here ú relay to cerebellum § medulla – somatic sensory relay ú autonomic sensory and motor nuclei spinal cord differentiation • caudal neural tube • gray matter – neurons o dorsal horns – sensory o intermediate zone o ventral hors – motor • white matter – axons o dorsal columns o lateral columns o ventral columns overview • forebrain – prosencephalon o telencephalon § cerebral hemispheres § cortex, basal telencephalon, olfactory o diencephalon – thalamus and hypothalamus • midbrain – mesencephalon o tectum o tegmentum • hindbrain – rhombencephalon o cerebellum o pons o medulla • spinal cord • ventricles CNS – • 7 major subdivisions o spinal cord o medulla o pons o cerebellum o midbrain o diencephalon o cerebral hemisphere – telencephalon • brain (hindbrain, midbrain, forebrain) • brainstem (medulla, pons, midbrain) somatic/autonomic nervous system • 4 divisions o cervical (C1 – C8) o thoracic (T1 – T12) o lumbar (L1 – L5) o sacral (S1 – S5 + coc1) • spinal nerves o dorsal roots § sensory § dorsal root ganglia o ventral roots § motor 11/4/15 2:16 PM 11/4/15 2:16 PM Auditory System 11/4/15 2:16 PM formation of sound waves • air compression increases pressure • rarefication decreases pressure • these both create sound waves • waveform characteristics o frequency = pitch or tone § higher frequency = higher pitch o amplitude/intensity = loudness structure of the ear • outer ear o pinna – directs sound o auditory canal • middle ear o tympanic membrane – vibrates at frequency and amplitude of the sound wave (translated into physical movement) o ossicles – small bones that connect eardrum to oval window (at beginning of cochlea) § malleus, incus and stapes § set up fluid wave within cochlea • inner ear o vestibular apparatus o cochlea – fluid filled § fluid wave (from ossicles’ pounding on window) at same frequency and amplitude cochlea • coiled tube like snail shell • 3 fluid filled chambers o 2 large – contain perilymph § scala vestibule § scala tympani o 1 small § scala media – cochlear duct (isolated from cochlea AND brain) ú within cochlear partition ú contains organs of corti (embedded in basilar) membrane ú has its own fluid - endolymph • helicotrema o apex of cochlea o connects scala vestibule and tympani sound transduction • organ of corti o located in scala media o hair cells § whatever singular cilia does, rest follow § at base of hair cells, synapse with axons in spiral ganglion neurons § synapse with ending of spiral ganglion neurons § inner hair cells – most important for hearing ú most of sensory signaling and transduction occurs here § outer hair cells – amplify sounds o basilar membrane o tectorial membrane o afferent axons • transduction o fluid waves – Reissner membrane o oscillation in basilar membrane (with hair cells embedded in it) o movement of hair cells o movement of stereocilia (within tectorial membrane – rigid membrane) • stereocilia movements o Resinners membrane is above and oscillatins o causes basilar membrane to oscillate the same way o hair cell cilia will bend in the opposite direction o basilar membrane oscillations cause forward and backward movements of the stereocilia mechano-electric transduction • opening and closing of mechanically gated potassium channels o toward long cilia à opening potassium channels o toward short cilia à closing potassium channels • opening causes influx of potassium à depolarization • causes opening of voltage gated calcium channels • causes glutamate transmitter release hair cell receptor potential generation • endolymph à high potassium and low sodium o +80mV potential o EK = 0mV • perilymph – high Na, low K o 0 mV potential • hair cell: -45 mV resting potential o reticular lamina separates hair cells • opening of K channels – depolarization • closing – hyperpolarization • repolarization o opening of K channels in base of hair cell • 2 different EK’s (1 at base, 1 at apex) auditory signals • sound waves o compression and rarefication o sinusoidal wave o sinusoidal wave in perilymph § mechanical pressure on oval window sets up fluid waves • opening and closing of mechanically gated K channels o depolarization and hyperpolarization of hair cells o reproduces sinusoidal wave up to high frequencies frequency sensitivity tonotopy • basilar membrane o narrow and rigid at base o runs whole length of cochlea o wide and flexible at apex • different frequency sensitivities o base sensitive to high frequency (due to high rigidity) o apex sensitive to low frequencies (due to lower rigidity) o basilar membrane animation • tonotopic organization of cochlea o tonotopic transmission to brain each hair cell synapse on spinal ganglia neurons • SO these ganglion cells toward apex getting lower frequencies, those toward base get higher 11/4/15 2:16 PM 11/4/15 2:16 PM Neurotransmitters 11/4/15 2:16 PM • criteria • 1. synthesized and stored in presynaptic terminal o immunohistochemistry - use of antibody to identify where neurotransmitters are (determines whether nt in vesicle) § main technique for nt location and whether or not chemical is neurotransmitter § generate antibody for chemical (by injecting animal with chemical to make antibodies – will stick to antigen sites when applied to brain slice) • 2. released from terminals with stimulation o chemical assay (take up ECF, assay for chemical) o determined by chemical response • 3. specific receptors on postsynaptic cells o neuropharmacology – using agonists or antagonist to stimulate or block receptors o autoradiography – using radio-tagged or fluorescent-tagged neurotransmitters to see where it sticks (to find receptors) • discovery of neurotransmitters • transmission of nerve signal: electrical or chemical? • experiment by Otto Loewi – 1921 (confirms neuron doctorine) o 2 hearts in separate chambers – connected by tube so ONLY fluid could flow (no electrical connection) o stimulation of vagus nerve of 1 nd o transfer of medium to 2 o results: st § 1 heart: decreased rate and contraction (vagus nerve stimulated) nd § 2 heart: ALSO decreased (after first one) – SO chemical connection between chambers through fluid(not electrical) § chemical transmission of signal transmitter – ACh (vagusstoff) • types: 3 classes • 1. small molecule nt (3 subgroups) o 1. amino acids § glutamate (excitatory) § GABA/glycine (inhibitory) o 2. ACh o 3. biogenic amines § catecholamines ú dopamine ú norepinephrine ú epinephrine § serotonin § histamine • 2. neuropeptides – all use G-protein coupled receptors (metabotropic) o peptide packaged into vesicles and released by neurons o release: § from neurons near synapses (acts as nt) § neurohumeral junctions (synapses on blood vessels) ú acts as neurohormone ú mostly contained in hypothalamus (controls ANS and endocrine) o types: § hypothalamic peptides § opiates § gut peptides • 3. unconventional nt o gases § NO § CO o lipids: endocannabinoids § made in plasma membrane § lipase converts lipid into endocannabinoid – released during production o growth factors/cytokines neurotransmitters are PROTEINS • 3 classes: o 1. cytosolic § synthesized by free ribosomes § transported by slow axoplasmic § fibrillar (cytoskeleton) and enzymes (metabolic triggers) § where small molecule neurotransmitters come from ú made from enzymes and precursors o 2. nuclear proteins o 3. membrane associated proteins § made by ribosomes stuck to RER § types: ú 1. integral and peripheral proteins ú 2. ER proteins ú 3. vesicle associated proteins, lysosomes • secretory products, enzymes synthesis, transport, packaging • 1. small molecule o synthesis of metabolic enzymes – work on precursors o cytosolic proteins taken, transported into vesicles o slow axoplasmic transport o synthesis of transmitter o uptake into synaptic vesicles o release • 2. neuropeptides o synthesis of precursor proteins o packaging into vesicles (into Golgi apparatus) o membrane proteins o fast anterograde transport along microtubules o gets to axon terminal, peptides ready in vesicles, ready for release § not recycled or charged within vesicles o cleavage of precursors (by enzymes) into final neurotransmitter product o release neurotransmitter fate at synapse • can be uptake by presynaptic terminal or postsynaptic o uptake from presynaptic goes into repackaging of small molecule neurotransmitter to recycle o diffusion terminates response o exocytosis triggers endocytosis o reuptake of neurotransmitter or breakdown of neurotransmitter § re-transported by vesicular transporters (on membrane) – put nt back into vesicles to recharge vesicles • neuropeptides usually packaged in dense-core vesicles (larger and more dense core than vesicles from small molecule transmitters) o these vesicles are black under TEM o vesiclaes are off active site – back a little further o released outside synapse (farther back) o responsible for volume transmission – not at synapse, but released into extracellular space § add to volume and increase concentration in peptide in cytoplasm § can be activating receptors anywhere in vicinity co-release (of both types of transmitters – peptides and small molecule) • co-localization of nt o small molecule nt and neuropeptides often located in same terminals • co-release: different locations of vesicles o synaptic vesicles (small) – docked at membrane o large dense-core vesicles – off membrane (out of active zone) § takes priming to get them to move to membrane • different exocytosis conditions o low frequency firing à low calcium concentration à small molecule nt release (readily releasable pool) o high frequency firing à high ca concentration à small molecule AND neuropeptide release § takes a lot of calcium to reach the area of neuropeptides (because farther back) § often, neuropeptides release modulates small molecule release (slow response modulates fast response) amino acids • packaged at axon terminal into vesicles • recycled at terminal into synaptic vesicles • glutamate: excitatory o usually extrinsic projection – project outside their area (all over the brain) § principal neurons o synthesis in terminal (precursor = glutamine) § catalyzed by glutaminase § recognized by vesicular transporter o release § postsynaptic receptors ú ionotropic: AMPA, kainite, NMDA ú metabotropic: mGluR1, mGluR8 o termination of actions: diffusion and uptake § taken up by astrocytes: EATT ú broken down into precursor (glutamine) through glutamine synthetase ú glutamine leaves astrocyte, goes into axon terminal via glutamate transporters ú recycled – made into glutamate again • GABA: inhibitory o usually inhibitory interneurons § intrinsic projections within a structure – link up principal neurons o synthesis in terminal § glutamate is precursor § catalyzed by glutamic acid decarboxylase (GAD)+ pyridoxal phosphate o packaging in vesicles by vesicular transporter o release § receptors: ú ionotropic – GABAA (Cl channel) ú metabotropic – GABAB (K and Ca channels - indirectly) o reuptake: § taken up into astrocytes and neurons § GABA transporters take them back to recycle § recycling breakdown § ACh • synthesis in terminal o precursors: acetyl CoA + choline (a.a) § via choline acetyl-transferase • release – receptors o nicotinic: ionotropic o muscarinic: metabotropic • termination: breakdown o acetylcholinesterase = acetate + choline o uptake of choline – choline transporter § re-synthesis of ACh § transmitter recycling • cholinergic systems o central ACh system: diffuse system – project axons out § 3 sources: ú 1. PMT (pontomesencephalotegmental) complex – basal forebrain projections ú 2. basal nucleus of meynart – cortical projections • higher, forebrain ú 3. medial septum – cortical/hippocampal projections • ACh fibers lost in Alzheimer’s • memory involvement • attention • Ach in Autonomic Nervous System o 2 neurons with each ganglionic system – 4 in total o thoracic and lumbar ganglia o postganglionic – very short neurons because located so close o 2 divisions: § sympathetic – ACh in preganglionic neurons ú postganglion uses norepinephrine § parasympathetic – ACh in preganglionic AND postganglionic ú located right on target organ catecholamines • dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline) • synthesis: all start from same amino acid precursor (tyrosine) o precursor = tyrosine (a.a.) o tyrosine hydroxylase à DOPA § L-DOPA treats Parkinson’s because it serves as a substrate for dopamine (to make up for dopamine loss) § DOPA crosses blood brain barrier (unlike dopamine) o DOPA decarboxylase à dopamine o dopamine B hydroxylase à norepinephrine o PNMT à epinephrine • mood, stress, fluid/energy homeostasis, reward systems • attention, arousal • released under emotionally charged conditions • autonomic functions • receptors – ALLL GPCR (metabotropic) o dopamine: D1-D4 o norepinephrine: metabotropic a(1 and 2), B(1 and 2) o epinephrine: metabotropic a(1 and 2), B(1 and 2) § both norepinephrine and epinephrine use the same receptors ú add diversity and flexibility to the system • dopamine: o diffuse modulatory systems o 3 sources: § 1. ventral tegmental area ú cortex frontal lobe projections ú schizophrenia (psychotic symptoms) ú reward § 2. substantia nigra ú striatum projections ú Parkinson’s • treatment can cause increase in dopamine in striatal cortex – can lead to issues ú motor control/smooth motor outputs § 3. basal hypothalamus ú neuroendocrine ú projects to poral circulation that irrigates pituitary gland • inhibits prolactin release (produces milk) ú regulates anterior pituitary ú prolactin secretion o dopamine reward system and drug abuse § cocaine inhibits reuptake of dopamine – heightened activation of dopamine receptors (because more dopamine left in the synaptic cleft) § same mechanism for SSRI’s • central norepinephrine systems – DIFFUSE projections o most areas of the brain have some norepinephrine o 2 sources: § pons: ú locus coeruleus ú dorsal noradrenergic bundle • cortical/cerebellar projections • spinal projections § medulla – brainstem NE system ú solitary tract nucleus (brainstem noradrenergic system) ú ventrolateral medulla ú ventral noradrenergic bundle – innervates basal forebrain, hypothalamus and thalamus • subcortical projections o diffuse projections involved in arousal and mood o some drugs that target serotonin and norepinephrine to block reuptake and increase receptor activation • norepinephrine in ANS o sympathetic: § produced by postganglionic neurons (projecting to target neurons) – targeted by beta blockers ú norepinephrine ú B receptors (fight or flight) serotonin (5-HT) • synthesis o precursor = tryptophan (a.a.) o tryptophan-5-hydroxylase à 5-hydroxytryptophan o aromatic L-amino decarboxylase à (5-HT) = serotonin o receptors (metabotropic - GPCR) § 5-HT1 through 5-HT7 § 5-HT4 thought to NOT be in the brain § 5-HT3 = IONOTROPIC • systems: o brainstem § Raphe nuclei (n=9) § diffuse projections ú brain – arousal, mood, sleep/wake cycle ú projections in spinal cord - pain regulation Neuropeptides: • ALL use metabotropic receptors!! • primarily located in hypothalamus o 2 types § 1. Neuroendocrine system ú pituitary gland – master gland ú releases neurohormones ú released into pituitary to regulate that OR into general circulation § 2. ANS – descending neuronal projections ú pre and postganglionic neurons are driven and controlled by projections from hypothalamus o hypothalamus = homeostasis control center/survival (due to combination of control of ANS and neuroendocrine systems) • Classes: • 1. magnocellular neuroendocrine cells (larger) o cell bodies are in the hypothalamus – project directly into pituitary gland o posterior pituitary § becomes part of brain due to cells– made up of axons of the neuroendocrine cells in hypothalamus § neuropeptide secretion directly into general circulation ú oxytocin • contraction of smooth muscle in mammary glands to eject milk (milk ejection reflex) • parturition (child birth) o contraction of smooth muscle cells in uterus to expel fetus ú vasopressin – anti-diuretic hormone (ADH), blood volume/osmolality • response to dehydration and drop in blood pressure o maintains water at kidneys • fluid homeostasis • BP regulation § neuropeptide hormones released directly into the circulation to • 2. parvocellular neuroendocrine cells (smaller) o different groups of cell bodies in hypothalamus § projects to the base of the brain o anterior pituitary control § 1. releasing hormones (or releasing factors) secreted from hypothalamus on pituitary hormones ú mainly neuropeptides • GnRH • TRH • CRH (corticotropin releasing hormone) o stress response o HPA axis – leads to corticosteroid secretion from adrenal glands • GHRH • dopamine ú inhibitory and excitatory § 2. pituitary hormones secreted from anterior lobe of pituitary ú prolactin ú FSH and LH ú TSH ú ACTH ú growth hormone 11/4/15 2:16 PM 11/4/15 2:16 PM
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