Lecture 12-21 (1) - Lecture 12 Wallerian Degeneration(1-6...

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Unformatted text preview: Lecture 12 Wallerian Degeneration (1-6) Destruction of the axon NOT the cell body Severing of the vertebrate peripheral nerve Distal axon degenerates Schwann cells (form myelin sheath) 1. Dedifferentiate (no longer specific cell type) 2. Proliferate 3. With invading macrophages, phagocytize the axonal and myelin debris. Cell body and nucleus swell Presynaptic terminals retract from the cell body. Several hours later the MOTOR axon sprouts (sprouts along the line of Schwann cells, along the basal lamina) near the proximal end and begins to regenerate If successful reconnection of axon with muscle cell body resumes normal position If connection NOT established: the cell dies rapidly. /7 Retrograde Trans-Synpatic effects Neurons that synapse onto the damaged cell are also affected by axotomization Synpase to cut axon is retracted Before retraction, synpase becomes weak: o Postsynaptic response to the same stimulation is smaller Presynaptic effect: less NT release implies a retrograde signal Postsynaptic effect: less receptors o Retrograde signal causes presynaptic terminals to retract If the neuron regrenrates and re-innervates its target, the synaptic inputs recover. 8/ Effect of denervation on the postsynaptic cells: Denervated muscle shows spontaneous, asynchronous contrations = fibrillation o Fibrillation is initiated in the end-plate but NOT response to Ach Contraction is due to Ach, but fibrillation is due to super-sensitivity to Ach (fibrillation is asynchronous contractions) With more time, the muscle begins to atrophy /9 EXPERIMENT: New AchR appear after denervation, spread along the muscle Setup- recording electrode records PSP, and a pipette with Ach. Used to localize the Ach response along the end-plate Super-sensitivity to Ach is due to an increase in number of AchR Sensitive areas to Ach increase until almost a uniform distribution of AChRs across the muscle surface. Researchers wonder if it is due to redistribution, but it is not! 1 10/ EXPERIMENT: Label the receptors with radioactive -bungarotoxin (binds AChRs) 1. 2. New receptors appear Another experiment: block AChRs synthesis with actinomycin 11-12/ Lomo & Rosenthal, 1972: Role of muscle inactivity in denervation super- sensitivity Question: is the axon gone or lack of activity in the muscle that causes synthesis of new receptors? Left axon in the muscle, but blocked AP propogation (7 days to inactivate the nerve) They see the increase in sensitivity (after 7 days the muscle becomes super- sensitive) Conclusion is the lack of contractions in the muscle, causes the increase in the AchRs synthesis LOSS OF THE SYNAPTIC INPUTS TO THE MUSCLE produces the super-sensitivity. 13/Role of muscle inactivity in denervation super-sensitivity: role of Ca2+ Influx of Ca2+ Activates PKC which Phosphorylates and inactivates myogenin (TF tha induce AChR synthesis) 14/Susceptibility of normal and denervated muscles to new innervation In adult mammals, innervated muscle fibers will not accept innervation by an additional nerve Unlike in GC development, re-innervation occurs at the original synaptic site guidance by endoneurial tubes (basal lamina, Schwann cells) of the former axon. 15-16/ Denervation-induced axonal sprouting; Denervated muscle can actively induce undamaged nerves to sprout new terminal branches Triggered by muscle inactivity Unknown molecular mech. 17/ Regeneration: Vertebrate PNS Schwann cells: Secrete trophic factors 2 Adhesion molecules ECM components secretion After regeneration has occurred, Schwann cells cease production of these molecules and again ensheathe the axon. 18/ Schwann cell axon regrowth LIF: from macrophages cytokine promotes Schwann cell proliferation Reg-2: from axon terminal cytokine, promotes Schwann cell proliferation Enhanced by LIF BDNF: [brain derived neurotrophic factor] from Schwann cell growth factor neurotrophic factor NGF [nerve growth factor]: from Schwann cell growth factor neurotrophic factor ApoE: produce by Schwann cell, protects against oxidative damage and promotes neurite (axon or dendrite) outgrowth and adhesion. 19/ BDNF, and NGF These are neurotrophic factors synthesized by Schwann cells Normally supplied by the target tissue to maintain the synaptic connection Held onto Schwann cells' surface by low-affinity BDNF/NGF receptor may help to sustain the factors along the desired growth path As regeneration progresses, Shcwann cells cease production of NGF and BDNF 20-21/ Specificity of reinnervation Functional recovery does not involve axon regeneration need appropriate reinnervation One mech: competition between axons : eg salamander muscles innervated by inappropriate axons will be eliminated after appropriate innervation occurs. In mammals: selectivity in reinnervation is less successful LITTLE ABILITY TO REINNERVATE THEIR ORIGINAL TARGETS FOREIGN nerves can be just as effective as original nerves If axon is crushed (but not cut) the original axon can successfully reinnervate its original target because it can travel the endoneurial tube 22-23/ Role of Basal lamina at regenerating NMJ Synaptic basal lamina: ECM of proteoglycans and glycoproteins 3 Surrounds muscle, nerve terminal, Schwann cell and dips into the folds of the postsynaptic membrane. In the cutaneous pectoris of the frog muscle After denervation there is death of the muscle and axon in the basal lamina But still have an anatomical structure (the basal lamina) The re-innervation was formed within/or region of the basal lamina Shows the signal for re-innervation is the basal lamina 2 weeks within the same basal alamina, there was new muscle 24/ Id of Agrin extracts of basal lamina mimicked the effects purified and characterized as Agrin During develp, agrin incorporates into the basal lamina 26/ CNS glial cells limit axon regeneration Spontaneous regeneration is almost abscent Motor neurons whose cell bodies lie in the spinal cord, can regenerate severed peripheral axons Axons of sensory neurons re-grow to their targets in the periphery but FAIL to regenerate in CNS Sensory axons regenerate toward spinal cord but stop growing when they reach the astrocytic processes at the CNS border. 27/ What limits regeneration in the CNS? Extrinsic factors: Inhibitory molecules creates envrio hostile for growth: CSPGs inhibitory molecule present in the ECM Nogo, netrin, ephrin present in adult myelin Astrocytes for a glial scar Intrinsic factors Injury associated signals Lack of growth associated proteins required to re-enter the active growth state Death of injured neurons LIF and Red-2 are not produced at the site of injury to stimulate regeneration 29/ The major components of the site of injury include and targets for therapeutic intervention: Myelin debris neutralize Ab, inhibit signal transduction Scar-forming astrocytes proliferation inhibitor, modulator of specific function Activated resident microglia steroids, autologous macrophages, t-cell based vaccinations 4 Infiltrating blood-borne immune cells Chondroitin sulfate proteoglycans (CSPGs) neutralizing Ab, receptor antagonist, degrading enzyme, inhibitor of matrix formation, inhibit signal transduction Other growth inhibitory matrix xomponents Lecture 13 Synpatic plasticity o Note: no glial scar in periphery 3/ Looking at the glial scar, refer to L12 notes. o o Astrocytes generate the scar Microglia are the resident immune cells of the brain roles in development but not typical immune response behavior, but after injury they react. Treatement to minimize gial scar through astrocyte: 1. Proliferation inhibitors 2. Modulator of specific function 5/ Figure 1 of Blesch and Tuszynski, 2009 o o Injuries within the spinal cord Mechanisms that can potentially contribute tp spontaneous, or experimentally enhanced plasticity after spinal cord injury o Rapid response unmasking = turning to a different inervation of the same effector (muscle) o Delayed response sprouting 5 6/ Delayed plastic mechanism a) Sprouting of lessioned axon to other supraspinal projection enhance descending activity b) Sprouting a propriospinal relay supraspinal lesioned axon sprout to a spinal interneuron forms novel intraspinal relay c) Sprouting of an unlesioned propriospinal axon towards deinnervated muscle unlesioned intraspinal neuron compensatory sprouting in response to loss of supraspinal input d) Sprouting of remaining supraspinal projection spared supraspinal axons can undergo compensatory collateral sprouting below a lesion e) Regeneration axon experimentally induced to undergo axonal regeneration through or around lesion site (most challenging) [is seen] 7/Clincial improvements 1. Use contusion model (bruising of axon, not cut) [there are different levels of bruising medium to severe. For experimental reasons, the more moderate contusion medl is more successful then severe, so severe is not used regularly. However, the severe is a better clinical model.] Replicability(funding) Size of model (human spinal cord is much larger then a mouse) therefore think to use dogs, cats Timing of the therapeutic intervention (highest rate of improvement right after injury occurs), but need to look at later time points, as is more clinical Confounding factor of variability in human trials [try to make more confounding models] 2. 3. 4. 5. Synpatic plasticity (SP) 10/ Plasticity is the capacity of the nervous system to change o Synaptic plasticity : capacity to alter the strength of synaptic transmission o Short-term, long-term how long the change in the strength lasts o Pre and post synaptic changes change can occur at either place o A change in synaptic efficacy/strength Can be: Hebbian (activity-dependent) or heterosynaptic (activity-independent) = [depends on various synapses] Note: faster a change occurs, general decays faster o o 11/How to test for synaptic plasticity o o o o Test strength of synapse: o Stimulating electrode in presynaptic cell o Recording electrode in postsynaptic cell Stimulation of presynapse causes NT release Postsynaptic binding of NT opens inon channels recorded postsynaptic The amplitude of the PSP is a measure of the strength of the synapse o Relative measure: No matter IPSP or EPSP, recording is always normalized to baseline before conditioning. Normalized to 1. 12/ o o o The arrival of individual AP is not typical Trains of AP are common Ongoing trains can have significant effects of the strength of synapse 6 o o Changes in the strength of the synapse are referred to as changes in synaptic efficacy Activity depenedent synaptic plasticity (Hebbian) when activity causes the change in synaptic efficacy. 13/ o o o Key to SP change in strength persists after the activity that induced the plasticity Change in pre or post [Ca2+] underlie most forms of synaptic plasticity Mechanisms are classified as pre or post 14/ train of presynaptic APs can cause SHORT-TERM PLASTICITY o o o Facilitation = increase PSP Depression = decrease in PSP Effect depends on synapse, and conditioning (frequency, duration) 15/ Synaptic Facilitation o o Appears instantly Due to increase in the mean # of quanta released (presynaptic plasticity); is though to be due to an increase in the probability of release Last for several millisencods shortest synaptic activity known o 16/ Synpatic depression o o o o o Due to presynaptic changes Lasts up to 6 seconds Thought to be due to the depletion of vesicles (docked and primed) Often cuased by tetanus stimulation Rate of depression depends on the level of tetanic stimulation 17/ Synaptic facilitation: due to residual Ca2+ left in the presynatpic terminal o o o o o EPPs from frog NMJ Amplitude of potentials increase during the train of presynaptic APs Effect outlasts the stimulus Performed with LOW [Ca2+]o; thus there were few quanta released avoids synaptic depression Test stimulus occurs after conditioning 18/ Synaptic depression o o o o o EPPs from frog NMJ Amplitude of potentials decrease during the train of presynaptic APs Effect outlasts the stimulus Performed with HIGH [Ca2+]o; thus there were maximal quanta released get to synaptic depression Test stimulus occurs after conditioning 7 19/ With normal EC Ca2+, there is first seen the facilitation, then the last test stimulus is depressed. 20/Short-term plasticity: summary o o o o Studied in the PNS, but ALSO occurs in the CNS Facilitation is due to increase in the mean number of quanta release; possibily due to residula Ca+2 in presynaptic cleft Depression due to depletion of vesicles Transmitter release is subject to two short-term modifications 21/ Augmentation intermediate facilitation (difference to facilitation is time scale) o o o o Slower phase of facilitation Repetitive stimulation also induces augmentation an increase in synaptic potential amplitude Augmentation comes on more slowly than facilitation(800 msec) and decays more slowly (5-10 sec) Due to increase in NT release 22-23/ Post-tetanic Potentiation (PTP) intermediate facilitation o o o o o Synaptic depression is often followed by an increase in synaptic potential amplitude Increase in synaptic potential amplitude due to NT release Due to in NT release Depends on Ca2+ entry Delayed onset max amp reached in seconds after stimulation ends and lasts tens of minutes 24/ EXPERIMENT: example of PTP in the chick ciliary ganglia o o o o o Potential recorded with an intracellular microelectrode Treated with curare (block AchR) to decrease EPSP amplitude Hyper-polarized cell prior to stimulation to prevent an AP Red asterisks is artifact Second slower depolarization is caused by Ach release and binding (red arrow) Tetanic Stimulus = 100 pulses/s for 15 seconds o 8 Lecture 14 Synaptic plasticity 2/ Long-term changes in signaling o o Studied and seen mostly in CNS 2 types of long-term changes: o LTP: long term potentiation o LTD: long term depression These are thought to be the cellular basis of learning and memory. 3/LTP & LTD o o LTP increase in size of PSP lasting hours or days, produced by previous synaptic activity LTD decrease in size of PSP, with same as above. o These are changes that depend on previous activity 4/LTP o o Bliss & Lomo in 1973, 1st described at glutamatergic synapses in the hippocampal formation Hippocampal formation lies in the temporal lobe; o 2 regions: hippocampus dentate gyrus anatomically together Hippocampus desirable for experiments: b/c synaptic transmission occurs through a directional circuit (anatomically direct circuit*) and it has a laminate structure of neurons. o *anatomically direct circuit = able to see all cell bodies and axons leading to specific other areas. Electrode placement can be placed with prior knowledge of the direction and location of the signal flow allow for strong conclusion. o 6/When did the hippocampus become intresting to study learning and memory? 1953 a bilateral medial temporal lobe resection was performed on patient H.M in an attempt to stop epileptic seizures post operation impaired anterograde memory o limited to inability to register new facts in long term memory above avg IQ 9 traditional trisynaptic pathway = solid arrows 1. axons in layer II neurons in the EC project to the dentate gyrus through the perforant pathway 2. dentate gyrus sends projections to the pyramidal cells in CA3 through mossy fibers (axons) 3. CA3 pyramidal neurons relay the information to CA1 pyramidal neurons through Schaffer collaterals pathway 4. CA1 pyramidal neurons send back-projections into depp layer neurons of the EC 5. CA3 also receives direct projections from EC layer II through the perforant pathway. 6. CA1 receives direct input from EC layer II neurons through the temporoammonic pathway (TA). NOTE: most experiments are done in vitro 8/EXPERIMENT: LTP in hippocampus of anesthetized rabbit (in vivo) Tetani stimuli (15/s for 10 sec) to PP; recording from granule cells in dentate gyrus LTP shown in all three synapses of the hippocampus (all glutamenergic synpases) 9/EXPERIMENT: Associative LTP: 2 synapses to same cell Rat hippocampal slice Intracellular recording from CA1 pyramidal cell 10 Stimulating electrode in 2 distinct groups of presynaptic fibers in Schaffer Collateral- commissural pathway Stimulation intensities are different: o Large EPSP from electrode 1 induced LTP with tetanic stimulation o Small EPSP from electrode 2 no LTP Results based on stimulus intensity not anatomy 11/ LTP requires increase in postsynaptic Ca2+ o Ca2+ enter through NMDA-glutamte receptors during LTP induction 12/NMDA and AMPA receptors Glutamate is the major excitatory NT of CNS 2 subtypes of glutamate ionotropic receptors postsynaptic o NMDA receptor higher Ca2+ conductance + blocked at rest by Mg+ Coincidence detector Open only when depolarized and activated by glutamate = stimulus at pre and post-synaptic simultaneous Blocked by NMDA o AMPA receptor Both cation channel Na+ and K+ with Ca2+ Activated by AMPA 15/ Proposed mechanism of LTP Activation of NMDRs Ca2+ influx activate calcium-clmodulin CaM activate CaM-dependent protein kinase 2 CaMK2 auto-phosphorylates, enabling it to stay active after Ca2+ have returned to rest 2 effects of CaMK2 has 2 main effects : Phosphorylates AMPAR = increase their conductance Mobilize reserve AMPAR to the membrane o During LTP effect occurs quickly 11 Main concern with LTP is high frequency stimulus to induce plasticity Hebb's postulate: learning and memory would involve synaptic strengthening elicited by coordinated firing of pre and postsynaptic cells 24/ SPM hypothesis (the synaptic plasticity and memory hypothesis) Activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation, and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed Testing: o can we have memory storage without LTP Block induction or expression of LTP in the hippocampus without doing anything else k/o is not good b/c don't know compensatory and other effects o show LTP is not necessary suppress LTP w/o affecting learning Figure 2 and 3 in Neves 2008 (next lecture) Lecture 15 24/ SPM hypothesis (the synaptic plasticity and memory hypothesis) Activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation, and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed Testing: o can we have memory storage without LTP Block induction or expression of LTP in the hippocampus without doing anything else k/o is not good b/c don't know compensatory and other effects o show LTP is not necessary 12 Figure 2 Neves 2008 suppress LTP w/o affecting learning Experimental vs learning induced LTP a) LTP induced in rat brain slices in vitro . Electrode in schaffer- commisural projection, recording in CA1 b) In vivo LTP induction by electroshock learning to dark area [ihibatory avoidance task], enhances LTP but occludes LTP induced by tetanic stimulation a. Training dependent synaptic enhancement occludes LTP induced by tetanic stimulation. Fig 3 Testing necessity: Abolish hippocampal cell assemble encoding a particular memory Arc/Arg3.1 are genes found to be expressed during LTP. Treatment with MK801 which blocks NMDA receptor stops expression of Arc/Arg3.1 (shown by GFP reporter disapperance). Alsostantic receptor is introduced under the promoter of Arc/Arg3.1 along with the reporter GFP. Cells that are induced by learning can be silenced by allostatin, which opens the allostatin GPCR inward rectifying K+ channel and hyperpolarizes the cell. After 7 days the receptor is internalized and degraded A new set of memory cells will come up with task B, which are silenced with allostatin, but the Task A memories are spared 12/Memory and cellular approaches to memory allocation in neural circuits (silva et al 2009) Wide evidence for how different types of memory engage different parts of the brain and how information in these regions is stored Recent finding suggest memory allocation is a set of specific mechanism that regulate where information is stored 13/Memory allocation 13 Memory allocation = set of processes that determine where information is specifically stored in a neural circuit o Cellular level determines which cells and/or synapse will be activated during the memory formation Open questions: o Does memory allocation occur at random? o Does memory allocation require competition btw cells o Does MA take place on different time scales? 14/Silva et al 2009 model of memory allocation in neuronal populations: Nave neural circuit is recruited to encode task A. Increase in excitability of task a encoded neurons likely involves them in encoding along with task B. As time progresses, excitation wanes, and task z encodes in an unrelated set of neurons o Consequence is task A recalls task B also 15-17/ Creb and memory allocation Training cuases increase in CREB = cAMP responsive element-binding protein o Regulates transcription of other genes + stability of synaptic plasticity and memory Hypothesis: CREB activated during learning triggers changes in the cell (increase excitability) that affect the chances of that caell to participate in subsequent memory. After intial increase in CREB, CREB-repressors that are also encoded in the CREB gene family, decrease the overall CREB levels. o Brings them to below basal levels High levels of CREB increase other proteins (eg Sch1b) that increase neuron excitability. Two meories acquired while CREB levels are high would be stored in overlapping populations of neurons o Timescale requires transcription of molecules and channels = days One memory could affect the allocation of the proceeding memory for many hours 18-19/ Model of memory allocation within dendritic trees After learning and subsequent potentiation of synapses, molecular components diffuse to nearby (10m) unpotentiated spine for a limited itme (10 min) o Temporary increase in probability that these spines will participate in subsequent learning CO-RECALL o Two memories aquired w/I min of each other may be sotred in similar populations of cells and nearby synapses = strong co-recall o Two memories acquired w/I hours, may be sotred in overlapping celluarl population, but not in nearby synapses = weaker co-recall Conclusions: 1. 2. 3. Mechanisms work on timescale to modulate allocation of memory a. CREB signaling, neurogenesis, synaptic selction Memory allocation involves many synaptic, cellular, and systems mechanism, regulated by many molecular processes Competitive mechanism affect memory allocation a. New dentate gyrus neurons, amygdala cells with higher excitability, synpases near previously potentiated synapses 14 4. i. These have competitive edge affect memory allocation over large timescales Memory allocation study of memory deficit a. Aging decrease excitability and rates of neurogenesis. Lecture 16 14/ Eric Kandel on memory Inertabrate learning and memory (not exclusive LTP b/c looking at behaivour too) Studied in Aplysia californica o 20, 000 neurons organized in ganglia Habituation o At synapse = depression o Behavior = habituation 17/ gentle touch on siphon trigger withdrawl of gills repeated touch reduces gill withdrawl by 1/3 o Short term habituation- 10- 15 touches within a few minutes Lasts days o Long-term habituation repeated touches for several days Lasts weeks Cellular mech: Caused by changes in the presynaptic axon terminal in the synapse btw the sensory neuron and the interneuron 9internruon reduces synapse on motor neuron/sensory neuron synpase o Inaccitavtion of Ca2+ channels at sensory neurons (due to depolarization) o Changes in # and location of synaptic vesicles o Result = less release of NT during habituation Share short and long term mech Sensitization PRESYNAPTIC changes Increase response to low intensity stimulus after exposure to high intensity stimulus o In Aplysia: short term sensitization involves secondary facilitating internruon btw tail sensory neuron, and the siphon sensory neuron synapse on the motor interneuron and the motor neuron Effect is on the presynaptic neuron o Long term mechanism involves CREB and other transcription factors. 15 Mechanism of short-term sensitization: 1. 2. 3. 4. 5. 6. 7. 8. Serotonin released by facilitating interneuron Binds to GPCR Activated GPCR activates PKA PKA phosphorylates K+ channel Inactivation of K+ channel AP duration Ca 2+influx NT release Lecture 17 4/ o o o o Sensory signals go 1st to the thalamus (relay station) From thalamus to primary sensory areas (different area for each sence) From primary sensory area to "higher" region of brain processing Processing: o Determine what signal comes from wher in brain o Incorportate prior learning, overall goals (determines if stimulus warrants further processing), general state of arousal 6/Sensory receptors o o Sensory receptor = sometimes the actual membrane receptor, other time refers to entire cell. o Define limit of sensitivity o Determine range of stimuli to be detected Adequate stimulus = stimulus energy (modaleity) for which the receptor is specialized to detect (for most receptors but not all) o Eye = light is adequate stimlus (but mechano response as well) o Nociceptors can sense multiple modalities Eg of a receptor without an adequate stimlus Receptor potential = electrical signal, transduced from the stimulus CNS recognizes the type of stimulus signal and its position by firing and circuit pathway 1. Anatomical location (not relevant to all modalites (eg hearing)) 2. The nature of the sensory ending Modality = kind of stimulus, not intensity o o o 7/Amplification = sensitivity o Stimlus amplified at the level of the receptor o Amplification from anatomy (eg ear) Fish electroreceptors can detect electrical fields 8/ o o o o Not all sensory receptors (SR) are classic neurons, not all fire AP, not all are afferent neurons ALL RELEASE NT Most are bipolar = sensory end and transmission end Photoreceptor synpase on a neuron that can fire AP 9/Short receptors: <0.1mm 16 o o o Eg: inner ear Sensory receptors located on sensory cells that have receptor potentials o Receptor potential spread passively from the sensory region to the synaptic region (Cells with short axons) o NO AP! Release NT tonically o 2 kids of signal: depolarization NT release hyperpolarization NT release 10/long receptor >0.1mm o o Receptor potentials trains of AP o Duration and frequency code duration and intensity of stimulus Cell body in the CNS 11/ Transducation of Mechanical Stimuli o o Transducation from cells in skin, muscle, joints, internal organs Receptive endings of sensory cells sense stimulus intensity and timing o Encode into receptor potential (similar to PSP) o RP is depol or repol o stimu intensity = RP amplitude 12/ RP Amplitude and stim intensity (stretch) o many sensory receptors = non-linear relationship btw stimulus intensity to RP amplitude and frequency o advantage = provide amplitude coding over wide-range os tim intensities log fnc scale of response to low stimulus o Disadvantge: always saturation area saturation at high intensity 13/Adapatation o o o o o high levels of stimlus saturate RP Amp stimulus maintained RP adapts RP reduces adapt quick or slow slowly adapting code stimulus duration rapidly adapt code change in stimulus (fastest can be 1 AP) o adaptation can be measured at AP level or RP level 14/ Crayfish Stretch receptor o Ideal b/c: o Cell body of the stretch receptor cell lies in isolation (not in ganglion) o 2 types of crustacean stretch receptors a. Rapidly adapting receptor responds to quick stretch quick decrease steady stimulus decrease response = adaptation b. Slow adapt receptor response well-maintained during most of prolonged stretch 17/ Olfactory 17 o o Weak in humans Processing centers near hippocampus o Memory olfaction>sound>visual 18-19/ o o o o o Smell and memory are linked Ability to smell and remember are separate Damage to temporal cortical region of the brain don't affect smell = prevent id of odor Whole memories with emotions can be prompted by smell. Unconscious. Innate ability to detect bad smell = babies 1 day old hate bad smell. 20/ o o o 100 000 olfactory receptor neurons with axons projecting to the olfactory bulb long cilia of the olfactory receptor extend in mucus (improves solubility of airborne chemical stimuli) o mucus protects sensory epithelium, washes away airborne toxic compounds Olfactory recetpors are continually replaced (1-2 months) o New receptors arise from a layer of basal cells in the olfactory epithelium Lecture 18 Olfactory receptor (notes in previous lecture notes): o o o o Receptor is a long neuron Produces AP Short life for a neuron (1-2 months) Mucus dissolves hydrophobic protein odorants 6/transduction mechanism in Olfactory Cilia 1. 2. 3. 4. 5. 6. Odorant bind GPCR Release fo -su Activation of AC [cAMP] Open non-selective cation channels (Ca2+, Na+, K+) membrane depolarization Ca2+-gated Cl- current enhance this effect PLC activated IP3 acts on IP3 Ca2+ channel 7/ Odorant specificity o o o o Discriminate odors due to thousands of different genes of olfactory receptors Each receptor recognizes a spectrum or odors rather then being highly selective Particular odorant receptor is found in a restricted area of the epithelium o Different families of R genes are expressed in zones extending along the length of the epithelium POPULATION CODING due to overlap in the spectrum btw odorant receptors 18 8/ Olfaction and gender o o Humans can learn new odor = sensitivity can be induced in humans o Eg develop smell for andostenone Humans enhanced smell sensitivity in reproductive females (5-fold) o Pari bonding and kin recognition 9/Ansomia o o o o o Sense of smel reduced or lost Cause traumatic head injury or virus (temporary) Congenital ansomia = receptor disfunction Can develop as a consequence of another disorder {Alzheimer's) Some ansomics suffer depression little can be done 10/ Taste o 75% we perceive as taste is smell, due to travel of molecules through nasal passage 11/Taste receptors o o o o o o o taste receptors = ciliated neuroepithelia cells found in taste buds regenerated throughout life SHORT RECEPTORS no axons Form chemical synapse with afferent neurites in the taste bud Sensory are: o Microvilli project from the taste cell in the taste bud where they are bound by tastants Convergence of info 10-50 receptor cells in one taste bud of different sub-type CONVERGENCE of information = hint for the reason we have large effect for combination of effects in the same food also why we have salt on food to enhance flavor (ie depolarization) depolarization leads to NT release o 12/Tastants are divided into: 1. 2. 3. 4. 5. salt direct flux of Na+ channel sour recognize toxin [H+] flow down gradient or protons block K+ channel bitter recognize toxins quinine block K+ channel or GPCR sweet GPCR umami GPCR glutamate receptor 15/ Molecular receptor of Chili o o not sensed by taste cells sensed by nociceptive receptor activated by capsaicin o capsaicin receptor is a Cal-sensitive cation channel 16/Nociceptive and thermal stimuli o o 2 kinds of skin temp = warm and cold warm and cold receptors do not sense extreme temperatures 19 17/Nociceptors o o painful heat leads to opening of nonspecific cation channels direct action + damaged cells release chemicals (eg ATP) o divided into thermal and chemical 18/ Visual system o of cells in the human cerebral cortex 19/ o o view eye with ophthalmoscope optic nerve is in the center of the retina o contains axons of the ganglion cells carry output to the brain o major blood vessels of the retina radiate from the center of the optic nerve 20-21/ o o o o o retina lines the back of the eye ganglion cells lie innermost in the retina to the lens and photoreceptors lie ourtermost light travels through thick retina before reaching rods and cones photon biochemical message electrical Fovea middle of what we see, densly packed with cones Lecture 19: 3/ o Bipolar cells = connect rods and cones with ganglion cells o Horizontal cells = connect synaptically in the horizontal axis synapse with both photoreceptors and bipolar cells o Amacrine cells = synapse with bipolar cells and ganglion cells o Connective tissue and structure composed of cells not part of neurnal circuit 4/ o Photoreceptors = rods and cones Note the location of cells in the light micrograph 5/The retina o Neatly layered o 3 layers of nerve cell bodies o 2 layers of synapses outer layer = rods and cones inner layer = bipolar, horizontal and amacrine cells ganglion layer = ganglion cells o 5 main classes of cell types 20 o photoreceptors rods (black and white; threshold of activation is lower = more sensitive = 1 quanta) (dark vision = conditions of low intensity) and cones (light vision) o bipolar cells connect photoreceptors to ganglion cells o horizontal cells form lateral connections btw photoreceptors and bipolar cells o amacrine cells form lateral connection btw bipolar and ganglion o ganglion cells o only amacrine and ganglion cells generate APs o many interneurons packed into the retina, intervening btw the photoreceptors and ganglion cells 7/Signaling in the retina o response to light rods and cones 8/ o o o o photoreceptors define the limit of vision rods and cones are densely packed fovea is specialized are containing densely packed cones used for discrimination only color here at night we see better in the periphery (everything around the fovea) blindspot point where optic nerve exits the eye no photoreceptors 9/ 3 principal feature of photoreceptor structure 1. 2. 3. Outer segment = light obsrobed by opsin (visual pigment) Inner segment = nucleus, ion pumps, transporters, ribosomes, mitochondria, and ER Synaptic terminal = CONTINUOUSLY releases glutamate; highly specialized terminal characterized by "ribbon" structure that contain the transmitter vesicles. 10/ Rods and Cones o o o Rods contain rhodopsin embedded in membranes arranged as disks (with not attachment to the outer membrane) Cones disks are infolded membranes that are continuous with the outer membrane each have differed opsin for RGB. Outer segment is connected to the inner segment by narrow stalk 11/Responses of the Photoreceptors o o o In the dark, inward current into the outer segment = RMP depoloraized -40 mV Light turns OFF the ongoing inward current Photoreceptors hyperpolarize with light = graded according to the intensity of the flash. 12/transduction mechanism 21 o o In dark mostly Na+ flows into the outer segment of both rods and cones o Light closes these channels Vm = - 80mV = hyperpolarize K+ channels are localized mainly in the inner segment (Not outer segment) 13/Structure of vertebrte rhodopsin in the membrane o o Opsins are GPCR that bind th chromophore RETINAL Light leads to a change in retinal, which leads to conformational change of opsin. Rhodopsin 11-cis retinal + photon All-trans retinal (in s) metarhodopsin I [rhodopsin bound to retinal] (ms) Metarhodopsin II [rhodopsin bound to retinal] (active conformation of GPCR) release all-trans retinal from opsin (min) 11-cis retinal [occurs in the pigment layer outside of the cell] Bleaching = when there is no 11-cis retinal to bind opsin, because all-trans retinal have been hyperinduced by starring into a strong light. 14/ Signal transduction in photoreceptor Rhodopsin + light Metarhodopin II activate G-Protein Transducin (GDP GTP) su transducin-GTP activate phosphodiesterase activates cGMP hydrolysis cGMP c-GMP dependent Na+ channel closure 15/Colour vision o 3 opsins in the 3 types of cones RGB o each receptor has specific range of light that they are activated with. o Not ON/OFF phenomena There are levels of activity %of activation Rhodopsin Blue Green Red 500 nm 420 nm 540 nm 555 nm Brain compares response from each of the three cones Brain receives PROCESSED information 17/ Retinal Processing o o o Photoreceptors communicate with ganglion cells via bipolar cells Modulated by : horizontal cells (first set of integration) Nearly ALL known transmitters have been found in the retina o Photoreceptor + bipolar cell glutamate o Horizontal cell GABA o Amacrine cell dopamine or Ach 22 18/ Ribbon synapses o Ribbon synapses : specialized endings that allow the continuous release of transmitter. Vesicles are all along the synapse and are more efficiently released o Found in rods and cones Vesciles docked for release along a flat organelle: ribbon 20/ Convergence and divergence of connections o Neurons converge and diverge extensively at every stage o 100 million rods and cones (CONVERGENCE) 1 million ganglion cell axons divergence: each ganglion cell axon supplies many genticulate cells 21/Receptive Fields o o o the area of the retina from which the ACTIVITY of a NEURON can be INFLUENCED by LIGHT Receptive field of retinal ganglion cell is SMALL CIRCULAR area on the retina RF in the visual system are complex: o Further subdivided into regions which either increase or decrease firing RF in many processing levels in the visual system Bipolar cells Ganglion cells Higher cortical areas Lecture 20 3/Receptive fields o o Area if the retina from which the activity of a neuron can be influenced by light Illumination outside a receptive field produces no effect on firing o Further subdivision Region increase firing Region decrease firing 4/Receptive field: Bipolar cells o o o o Each bipolar cell receives its direct input from either rods or cones Rod bipolar cell 15-45 rod photoreceptors Cone bipolar cell 5 -20 cone photoreceptor o Midget bipolar cells of the fovea input from a single cone, leading to the highest acuity Photoreceptor- bipolar Synapse: excitatory or inhibitory glutamatergic synapse o Depends on receptors on bipolar cell (large role on receptive field) 5/H and D Bipolar cells (THERE ARE MANY NOT TALKED ABOUT) ie there are more than two types of bipolar cells Bipolar cells H Decrease tonic release by illuminated photoreceptor HYPERPOLARIZE bipolar cell Synapse Excitatory (so less release of glutamate causes less release of glutamate on ganglion = 23 D less production of signal in ganglion cell) Decrease tonic release by Inhibitory (so less release illuminated photoreceptor of glutamate causes DEPOLARIZE bipolar cell release of glutamate on (removal of inhibition) ganglion = AP production of signal in ganglion cell) 6/ central light Annular illumination On or off depending where illumination induces ganglion firing Off-center On-center H Hyperpolarize Depolarize bipolar (inhibit bipolar ganglion firing) D depolarize Hyper-polarize 7-8/Horizontal cells: continuous inhibition o o o o o o Response of bipolar cells to illumination is modulated by horizontal cells HC receive input from many photoreceptors HC respond to illumination of PR by hyperpolarization (due to less glutamate release from PR) HC are electrically coupled with each other HC is influenced by light shone on a large area of retina b/c of current flow from its neighbors HC release GABA onto bipolar and PR in the dark o Thus depolarization of the PR in the dark is antagonized by inhibitory input from the HC 9/-ve feedback loop onto PR from HC Illumination PR hyperolarize = glutamate HC hyperpolarize = GABA other PR depolarize 10-11/Off-centre bipolar cell (H) -mediated by HC Center light PR hyperpolarize glut on bipolar and HC H bipolar hyperpolarize HC hyperpolarize but not much o HC receive hyperpolarizing input, but only from a few receptors, therefore small effect, as is the negative feedback on central receptor 24 Annular light PR hyperpolarize glut on bipolar HC hyperpolarize GABA on PR center PR depolarize (removal of inhibition) o Depolarizing feedback is minimal on the surround receptor, which are being strongly hyperpolarized by illumination o Center PR release GLUT and depol bipolar cell 13-16/ Receptive field: Ganglion cell o ON center cells respond best to a spot of light shone onto the central part of the receptive field o Illumination of the surrounding area decreases the firing of APs Illumination of the entire receptive field elicits weak discharges because centre and surround cancel each other. OFF center cells decrease firing of APS with the central area illuminated o Light shone on the surround causes excitation Effect is not all or none Ganglion cells fire AP at rest Receptive field is mapped by correlating light shone on the reina with increase or decrease in AP firing of a ganglion cell Neighboring fields collect information from similar but not identical areas of the retina o 0.1 mm of light will activate many ganglion receptive fields THROUGHOUT the visual system: neurons processing related information are clustered together (more so then convergence) o Size of the receptive field is smallest in fovea and largest in periphery ANOTHER LEVEL OF PROCESSING: ganglion cells can be receptive to movement!! o o o o 17/Anatomical Pathways in Visual system o o o Optic nerve fibers arise from ganglion cells in the retina and end in the lateral geniculate nucleus (part of THALAMUS) LGN projects to cerebral cortex Output divides at optic chiasm o Right side of each retina prjects to the right LGN Thus the right visual cortex receives information from the left half of the visual field Right brain damage = loss of left visual field o Large crossing with animals that have eyes on side of head? 19/ LGN o Retinal ganglion cells project to the LGN o Form retinotopic map (adjacent points in the retina project to adjacent points on the corical surface) o 6 layers in the LGN each is innervated by ONE of the eyes receive input from distinct subtypes of retinal ganglion cells o CENTER-SURROUND receptive fields (in LGN) like those of the retinal ganglion 25 20/Visual field Maps in the LGN o Highly ordered arrangement of receptive fields o Order from eye o Order from different type of ganglion cell Ie ganglion cells for color, or for movement Located together in specific areas of LGN o ORDER IN FUNCTION Retinotopic map o Neighboring regions of retina make connections with neighboring regions of LGN o FEW CELLS devoted to peripheral retina Receptive fields properties similar to ganglion CENTER ON and CENTER OFF (center surround) = not a lot of processing on the way to the LGN o Ordering and antomy arriving into LGN, provides for processing in the visual cortex. Anatomical basis of parallel processing of information. Process in parallel phenomena linked in terms of function o o Fovea projects onto a large portion of each LGN layer o 21/LGN-VISUAL CORTEX o o LGN project to V1 (striate cortex) to get retinotopic map Receptive fields of cortical cells don't have center-surround organization o RF is lines and edges Adds level of visual analysis o Six layers of V1 with specific organizational properties Anatomical order for different function o Each vertical stack of cortical cells functions as a module Takes input from one location in visual space and forward the processed info to secondary visual areas 23/ HUBEL and WEISEL o 24/ o o o o V1 receives input from LGN V1 sends to V2 Areas V1-V5 perform different types of analysis Retinotopic map is conserved in each area. 1950s, visual cortex of cats and monkeys o V1 responds to light lines and angles 26 Processing of visual SUMMARY Bipolar cells mediated by HC Ganglion cells LGN (6 layers) Off-center (H) and on-center (D) o On center and Off center o Function association (movement, color) o Center-surround receptive field (similar to ganglia) o Retinotopic map o Beginning of parallel processing o Highly order o Order by function o Retinotopic map o RF is lines and edges NOT Cen- Surr o Order by function V1 (6 layers) Lecture 21 2/ review from last lecture visual field, processing goes to the contralateral side of the brain. In a stroke. In V1 w still have areas specific for each of the eyes, still no convergence/clustering of information from all visual fields. This only happens at higher visual fields. 5/Figure-ground alternation o o By "focusing" on one object, the other becomes background. Science tries to dissociate the visual processing from the visual input. This is to determine the area of perception. 6/Winner-takes-all o o Illusion tell us that the process of visual organization is dynamic (means not deterministic process it can change along the way) and related to continuousness Winner-takes-all theory of perception (perception = most studied process in humans) o Only part of the image can be selected as focus point 7/ Perception o Visual perception (what we are aware of seeing) is thought to occur through a single hierarchical system of cells that processes info from the retina to the cortex. 8/Grandmother cell? o Neurons become more specialized with increased processing in the visual system. 27 9/Face detecting cells o o Not enough neurons for the grandmother cell theory There are "face detecting cells" that respond to faces (the rate of action potential increases if there is a face), even discriminating between faces in different orientations 11/Why do so few scientists study consciousness? 1. 2. Consider consciousness to be a philosophical problem Premature to study a. Consciousness is not clearly defined b. Neural correlates of consciousness are not well characterized. 12/Consciousness defined o Although argue this is premature: o Conscious: Having an awareness of one's environment and one's own existence, sensations, and thoughts. 13/Different aspects of consciousness: o o Being conscious (state of being awake, sleep, etc.) Being conscious of X (green apple vs orange) 14/The ascending reticular activating system role in general level of consciousness o o Enabling factor: level of consciousness doesn't tell us directly about the conscious experience Ascending reticular activating system mediates out level of consciousness. o It is an organization of neurons from the midbrain to the thalamus that project widely to cerebral hemispheres maintain alert state. 16/ current status of the neurobiology of consciousness is at the level of determining neural correlates of consciousness. Where can we correlate consciousness of X with areas of the brain (looking for correlation and causality of response in the brain to object X) 17/NCC Neural correlates of consciousness o o NCC = specific patterns of brain activity that correlate with particular conscious experiences, ie visual consciousness. Neuroscientists will need to determine: o Neurons associated with NCC o Connection btw then o Firing patterns o How NCC neurons differ from other NS neurons. 18/ Method of NCC measure: o o Box 1 of paper (not advantage or disadvantage but can record single neurons or any electrical activity which can be compared) Record activity of single neuron electrodes are inserted into the skull and brain (risk of injury and infection) [these could be epileptic patients] 28 o o Electrodes record: o EC single-neuron activity, o multi-unit activity o local field potentials Major issue: o How each technique reflects physiological neuronal activity o And relate to non-invasivie measure of brain activity Ie scalp electroencephalogram (EEG) Functional neuroimaging (fMRI) 20/Does the NCC for vision reside in V1? NO o o V1 is lowest cortical visual area Damage to V1 report no conscious visual experience even thought eh blindsight phenomenon exist (this is a processing problem, not in the retina). o This is the ability of a person with a V1 lesion to guess the orientation of objects, even though they are blind Suggests V1 needed for normal vision but may not be NCC of vision. 21/ V1 does not project to the frontal lobes (where cognitive processing occurs) o Thus V1 required for normal vision, not NCC 22/ Psychophysical evidence consistent with V1 not NCC Can't Id the eye which stimulus is present, even though V1 contains neurons that receive input from one eye only Blinking significantly alters response of V1 cells but visual experience is contious and uninterrupted Microsaccades also do not alter visual perception however V1 activity is significantly affected by them Lecture 22 2/ Dreaming and NCC o o o o o Visual experience without input = no input processing Is V1 an NCC? Brain activity in humans is measured with fMRI during REM shows V1 and surrounding activity is suppressed (normal activity during non-REM sleep); there is an increased activity in the intermediate visual areas fo the medial temporal lobe. Not dreaming is associated to damage in the frontal or parietal lobe (suggests these can be NCC) Pateints who have lost V1 = continue dreaming visually 3/V1 is not well correlated with conscious visual perception o V1 neurons have activity patterns that do not correlate with our conscious visual experience. o Changes in conscious perception can occur in the absence of activity in V1 o Example: BINOLCULAR RIVALRY 29 "Binocular rivalry has proved to be a powerful paradigm with which to study the neural correlates of conscious visual experience" o Activity in V1 is not sufficient to explain conscious perception. o bi-stable visual perception = brain super-imposes two images. 4/BINOCULAR RIVALRY o o o when two different images are presented to a corresponding areas of the two eyes, the images compete for perceptual dominance each image is visible in turn for a few seconds, while the other is completely suppressed. Perceptual transition btw each monocular view occur without any corresponding changes in the physical stimulus. This phenomena allows experimental dissociation of NCCs from changes to the physical stimulus Only way to be able to recognize NCC is when we can dissociate the perception process from the input process. 5/ Anatomical hierarchy of visual areas in human and non-human primate o o o Beyond V1, the distributed visual cortical areas analyze different aspects of the visual scene. In non-human primate there are dense interconnections btw these areas, but we don't have enough data to say for humans. Damage to cortical areas responsible for analyzing specific features leads to a deficit in consciousness of these features in an exclusive manner. o Eg, damage in V4 that determines lines damage = loss of this perception. 6/ there is an anatomical connectivity of the macaque (monkey) visual cortex. 32 visual cortical areas, 2 subcortical visual stages, several non-visual areas connected in 187 anatomicall link, most reciprocal. 7/ Single neuron activity in human temporal cortex correlates with awareness. o o o o Subject with electrodes in brain Shown human face and ball Establish response of a single neuron response. In the second state, subject closes eyes and is cued to imagine face or ball. 8/The timing of neural activity o o o Main hypothesis anatomically localized neurons with a level of spiking activity mediate awareness However, overall spiking activity may not be relevant neural correlate Awareness might be associated with a type of neural activity (ie oscillatory or synchronized discharges) TIMING 9/Synchronization o Eg: selective attention synchronizes evoked activity in the visual and somatosensory cortex 30 o o However, no clear evidence that disrupt synchrony would impair perception Difficult to address empirically Timing with perceptual changes o Looking to see if specific time for the activity relates to it's relevance for perception. 10/ Parietal and prefrontal cortex o o o Neuroimaging studies suggest that activity in the parietal and prefrontal cortices is associate with visual awareness Areas active during perceptual transition (eg binocular rivalry, face/vase illusion) Regions might be causally associated with the generation of transitions btw percepts 11/areas that show activation correlated with changes in visual awareness. Prominent clustering of activation in the superior paritetal and dorsolateral prefrontal cortex 12/ Future direction o o o o Focus on id reliable neural correlates of consciousness (NCC) in vision Conscious and unconscious neural processes have to be dissociated Characterize more fully the functionally specialized areas of the visual cortex with the nature of the NCC (eg is it the intensity of the activity that is important, or is it the timing of the activity) How does cognition (thinking, learning, etc) interact with visual consciousness to produce large-scale integration resulting in phenomenal awareness. 31 ...
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