BIO 400: Final Exam Study Guide
BIO 400: Final Exam Study Guide BIO 400
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Lecture 1 The process of memory & Learning: ● study of the brain and how adaptive behaviors affect human nature ● Hippocampus is responsible for new memory formation” ○ STM ( working) → LTM Evolutionary Constraints: Associative vs Collectivistic Learning ● Associative unprepared, natural animal behavior ● Connectivistic prepared, learning for a purpose 2 Types of Learning: 1. Preparedness: info easily retained & absorbed (LEARNING WELL) ○ Bowet immune system has learning memory i. discovered antibiotics ii. turned light on to see if mice would run to it 2. Unpreparedness: can’t learn & retain info (NOT LEARNING WELL) ○ Thorndike cat couldn’t associate ball with door open ○ cats were UNPREPARED to scratch to get food ○ cats were PREPARED to pull lever to get food Conditioned Learning: stimulus response → reward ● Generalization gradient range of response due to stimulus Pavlov: dog with bell salivates to food = training Latency Learning: learning without a purpose → problem solving: Spatial memory Toloman: rate maze study→ spatial memory with environmental cues found where but not how or why rat solved task sheep with electrode on hoof ● “animals do what they ought to do”: ○ if they think food is there it will run to it Tinberg= bees have spatial memory Watson= shock with light to mice, adjusted intensity Anthropocentricity: ● regarding humans as the central element of the universe ● interpreting realityexclusively in terms of human values & experience Double & Triple Dissociation Lesion Experiments: 1.Erik Kandel lesion study ilanguage acquisition areas ○ Wernicke's speech use ○ Brocas understanding speech ● found l ocalization of functions → modern phrenology ● “discrete localizations in the brain provide elementary connections” 2.Sir Charles Sherrington reflexes study ● contradicts ideology of conditioned learning because behaviors can be controlled Operational DefinitionA decided way to measure something objectively. Example: “Memory is measured by how long the rat stays in each arm of the maze without food.” Lecture 2. Evolution of adaptive behaviors: Behavioral plasticity based on experience in natural environments & Implications for biology of neural plasticity ● Digger Wasp ○ Wasp leaves nest, does figure8 orientation flight goes to find food. ○ Brings food back to nest ○ When landmarks around nest are moved, wasp follows landmarks rather than nest location. ○ Changing landmarks reveals that wasp r esponds to landmark arrangement rather than type of landmark. ○ Conclusion: Wasps use patterns/configurations of landmarks to locate their nest. ● Gobiid Fish ○ Twice a day, they map the ocean floor depressions. ○ When the tide goes out, gobiidae are trapped in tidal pools. ○ If a threat is presented, the gobiid makes a calculated projectile jump to another pool. ○ The gobiid cannot adjust in midair, so the leap must be perfect or else it will not land in the pool. ○ Conclusion: The gobiidae can map and remember exactly how far the next tidal pool is to escape from threats. They can jump from pool to pool until they reach the open water and fully escape. This shows adaptability to the adverse situations that the fish encounters. ● Blackcapped Chickadee ○ Bird makes caches of food before winter ○ Goes back and finds them in the spring ○ Memory of caches is so extensive that it can remember up to 100,000 caches of (stored) food. Lecture 3 Evolution of brains ● Main Points: ○ Evolutionary constraints on learning, memory, and brain plasticity. ■ StimulusResponse (SR) learning is too simple to explain real learning. ● a.k.a. associative or connectivist learning ○ Individual constraints on learning ■ Personal histories matter (ADHD, learning disabilities) ○ Phrenology contemporary neuroscience Lecture 4 Best and worst of memories ● William James Features of Consciousness: ○ Every thought is part of a personal consciousness. ■ This consciousness is selfcontained and isolated from intrusion. ○ Within each personal consciousness, states are always changing. ■ Once something is experienced once, it cannot be experienced the exact same manner again. ○ Within each personal consciousness, thought is sensibly continuous. ■ There can be no distinct breaks within a single mind, rather a felt, experience continuity. ○ Appears to deal with objects independent of itself. ■ Not only knows the things that appear to it, but “knows that it knows them.” ○ Always acting to select from myriad of sensations impinging on an individual. ■ Decides what is relevant (presents these) and what is irrelevant (suppresses these). ● Williams James says: ○ Everyone has a completely unique experience (past, present, future) that modifies current experience in the present and future based on preexperience. William James continuity of consciousness varies by species & experience ● consciousness = personal (self contained), always changing ( no 2 experiences are the same), continuous experience, aware of mind vs. external world, senses help process actions ○ Flashbulb memories memory is strong because emotional content ■ adrenal theory of memoryhowever these change over time ● Chicken vs Egg: preconceptions sometimes override later findings ○ ex. age of football players show later cog. impairment severity ranges Aristotle“mind is in the heart” ● complex nervous systems: ○ lesion study with decapitated bee still flew ○ organ study with turtle heart beat in seawater after removal ○ correlational study observed people ● I <3 U: people associate love with the heart ● love is from the heart ● heart warming , loving Lecture 5 Tasks, operation definitions Place Training→ environmental cues objects in room remain same memorize where food is in reference to objects in room Response Training→ direction of path turn right to get food no matter where you are trun right for food Dual Solution Task: ● Response vs Place (above) Conditioned Cue Preference: given a cue to solve task ● hippocampus sensitive place preference win/stay : 8 arm maze Test:learning phase ● Day 1: solve maze without food ● Day 2: placed on specific arm of maze with abundance of food ○ barriers to prevent from going to others Training: ● repeat test for 7 days Results: ● control remove objects that previously blocked food during training ○ signifiesobject recognition memory → shows amygdala & hormonal response → increases release ofAch Lecture 6What can we study and what does it mean? 3 ways of Studying Behavioral Adaption: 1.Loss of Function Studies remove a gene/ structure & see what happens ● Lesion studies good for studying multiple memory systems ○ shows independent memory formation and interactions of memories ○ good at spatialrecording “the where” 2. Gain of Functionused to balance the loss of function ● superior autobiographical memory/ Hypermnesia : Jill Price & Mr. S ○ remember everything, with high emotional context and in chronological order ○ hard time abstract thinking, low emotions & creativity ● Differences in their brain composition: ○ Colocate Nucleus: 78 x bigger than normal people ■ involved in OCD ■ categorize events ○ Temporal Lobe ■ also enlarged ■ memory storing involved 3. Observation/ Correlation: look for a change ● TMS lesion studies of temporary damage OR observe abnormality ○ H.M . lesion in corpus callosum/ removed temporal lobe → retrograde amnesia ( can’t remember events prior to event) ○ Clive can’t form new memories (30 second memory) → anterograde amnesia ○ Foreign Accent Syndrome (cerebral vasculitis) disease where the language are of the brain is deprived proper nutrients from the blood, causing permanent damage in the language acquisition area. Patients will lose speech and regain language with a foreign accent Lecture 7 Multiple memory systems 1: Hippocampus, striatum, neocortex Brain Anatomy: ● hippocampal memory formation; figures out the processing of learning Experiments: slime mold no brain or nervous system “ external memory” slime mold finds shortest route between two points C. Elegans total of 302 neurons (seems simple actually complex) ● Purkinje cells ○ in cerebellum largest neurons in the human brain ■ part of the dendritic spines ○ Glutamatergic synapses : excitatory ■ each cell has millions of synapses ○ Aging? Lecture 8 Multiple memory systems 2: Amygdala ● Thigmotaxis: ○ behavior elicited by placing rodent in cold bath ( Dual Solution Task) ○ stress from being unable to find platform escape ○ increased stress causes the animal to circle the periphery of the maze→ hormonal response→ adrenaline release ■ circling behavior & memory enhancement ● Radial Arm Task (Olton) ○ Rats placed in maze with 8 possible arm choice in a circle ○ Must figure out where food is without checking the same arm multiple times ○ Going back to a previously checked arm would be considered an error Professor Gold’s Experiment rat CA 1 neuron PLACE CELL FIRING action potential goes off in specific places CONTINGENCY PLACE CELL can tell what direction animal will go after reaching place cell → predicts next or likelihood of the behavior Lecture 9 Multiple memory systems 3: Neurochemical modulation across multiple memory systems Interactions of Memory Systems: Place Fields many neurons activating & strengthening synapse ( part of LTP) ● develop within minutes ● persists for months Grandmother Cell: ● not just one cell tells everything about something ● multiple cells represent “grandma” ● damage to one grandmother cell causes a complete loss in function Ex) voice, laugh, smile, house smell Independent Multiple Memory Systems 1)Win Shift (PLACE) Hippocampus spatial memory with environmental cue only the trails with light have food 2)Win Stay (RESPONSE) Striatum problem solving food is randomly put in 4 out of 8 arms 3)Conditioned (CUED PREF) Amygdala animal is switched between having food one day and having no food the next day caudate nucleus = striatum= corpus striatum Formix: major input into HC leisioned to disconnect the hippocampus and induces communication Lecture 10 Multiple memory systems – neurochemical coordination Microdialysis:Tells the concentration of a molecule of interest within a brain area do a surgery on the brain to determine concentration of a brain chemical put the probe in the brain inject any neurotransmitter (anolyte) in the probe which expels in the brain perfusing different concentrations of neurotransmitter so the concentration in the brain and the conc in the probe is equal net flux = 0 Zeronetflux method: During microdialysis, at least 4 different concentrations of analyte are used, state where the the rate of neurotransmitter leaving the probe is equal to the rate entering DUAL SOLUTION TASK: → use a T shaped maze to train animals (rodents) ● Train: ○ rat placed at start arm and can go either left or right to find the food ○ cues are on both arms and rat associated cue with food ● Test: ○ put rat in maze with cue on one side and nothing on other side to determine strategy used to solve task ○ PROBE TRIAL: ● compare if animal used cue or spatial awareness Results: Place vs Response. → There is no difference in learning rates between Old and Young rats. They just prefer different methods of achieving the goal. ● Young Rats prefer using place strategy (hippocampus) ● Old Rats prefer using response strategy (striatum) → Damage OR repetition of trials ( training) increases Ach levels→ causes switch from place to esponse Lecture 11 Plasticity and memory how it is formed: Consolidation of the changes in plasticity and memory Stimulus→ Sensory Organs(Eyes,Ears,Touch) → sensory memory → short term memory → Llong term memory. Sensory Memorymillisecond to 1 second Short term memory seconds to hours Long term memory days, weeks, years Long lasting memoryLifetime Serial model of memory consolidation everything goes in order Stimulus → sensory organ → sensory memory → shortterm memory (some lost before converted to LTM) → longterm memory → conscious thought STM DECAYS RAPIDLY Vs. PARALLEL AS YOU LOSE SHORT TERM MEMORY..LONG TERM IS FORMING. Anterograde amnesia is loss of the ability to create newmemories after the event that caused theamnesia , leading to a partial or complete inability to recall the recent past, while longterm memories from before the event remain intact. ( Clive) Retrograde Amnesia: is a loss of memoryaccess to events that occurred, or information that was learned, before an injury or the onset of a disease. ● often temporarily graded (timedependent); subjects are more likely to lose recent memories (closer the traumatic incident) than those in the distant past → WW2 soldiers Retrograde enhancement of memory: posttraining via temporal gradient ● training → wait up to 6 hours → treatment: damage brain →wait more than 24 hours → test ● RESULTS: enhancing memory after the experience 1. INHIBITORY AVOIDANCE TRAINING: Hippocampus & Amygdala Studies ● Stay in the light area the mice have to learn that the dark area sho them ● Retrograde Amnesia Gradient: recent memories are more likely to be lost than the more remote memories. ○ the variabilit in retrograde amnesia gradients is the degree of memory loss ○ this is determined by the ECS severity & period between training and shock →the variability in the temporal RA gradient means NO single gradient equals the time for memory formation = memory consolidation time ● Short term memory decay gradient: ○ treat first and see how long it takes to consolidate the memories. ○ give Amnimyocin (PSI) Injection before HC or Amygdala training → the variability in decay gradients means there is NO single gradient for longterm memory consolidation = memory consolidation time ● shows different decay rates ( from .5 hours → 48 hours ) Protein synthesis inhibition can impair both shortterm memory ● PSIs do not impair memory for training with high footshock, for extinction training, olfactory memory. ● A function of brain system more than treatment ○ Particularly when viewed in the context of the rapidity (within minutes) with which brain structure can change, the need for the three Ts transcription and translation and transport – to cause these changes seems unlikely. Theory of Rapid Forgetting : with Inhibitory Avoidance Task: Young vs Old : aCSF Artificial Cerebrospinal Fluid) ● Retention Latency of light/dark task in seconds vs. the aCFS or Glucose injection ● Young had good retention for both, old just with glucose → may vary and can be changed Spontaneous Alternation Task: on Extracellular Glucose ● depletion shown during test time of task in both young and old, but drastically in the old seen in the hippocampus region ( sensitive to glucose) → suggests liver function damage causes blockage of energy storage ● offer a promising approach to ameliorate agerelated increases in forgetting. Our results suggest that cognitive functions in older adults are remediable simply if adequate glucose is provided to the brain. This research may open new avenues for development of drug treatments or lifestyle interventions for agerelated memory loss that target regulation of neuroendocrine response. The application of endocrine studies to examine bases for agerelated memory impairments will likely propel these developments, as might experiments that point to altered mechanisms of glycogen storage, metabolism, and delivery of intermediary substrates in the periphery or in the brain. Pharmacological control Experiments: 1. Lidocaine injection inactivates hippocampus ● Improves Response Tasks ● Hinders Place Tasks 2. Acute Stress ● Improves Response ● Hinders Place → The research described here provides evidence for neurochemical mechanisms that control the balance between multiple learning and memory systems. These mechanisms are subject to pharmacological control, as evidenced by the effects of direct brain injections of glucose into specific brain regions; similar results are also seen with neurotransmitter receptor agonists and antagonists. For acetylcholine, it appears that both hippocampal and striatal tasks result in increases in release of the neurotransmitter, but that the patterns of release change as rats progress through different stages of training reflecting changes in the use of different cognitive strategies and attributes during training. Damage Amygdala Can’t do CCPHippocampus works harder to compensate In CCP the hippocampus releases a lot of ach...therefore it beats out the amygdala SIngle trace Hypothesis of Multiple memory systems: ● Attempted to describe a model in which it is not necessary to postulate a STM process to account for available data. ● For longterm use of experiences, it seems likely that the available consequences of experiences began to provide a brain state that determined longterm memory storage. If the physiological consequences of an experience are considerable, the organism would best retain that experience for long periods of time. If the consequences are trivial, the experience is best forgotten quickly. → Thus, timedependent memory processes may be the result of the development of a mechanism with which organisms select from recent experiences those that should be permanently stored. READING: “Memory Enhancing Drugs” Paul Gold Smart Drugs any memory enhancing drugs with glucose uptake system ● ex. amphetamine augments catecholamine functions by blocking reuptake mechanisms. adrenergic, nicotinic, and glutamatergic receptor agonists act largely on postsynaptic receptors to mimic the action of the neurotransmitters norepinephrine, acetylcholine and glutamate ● CONCLUSION: Findings such as these suggest that the temporal and spatial properties of neural activity may not apply to all neurotransmitters in all brain areas and may instead function much like local hormones, changing the functional state of the areas they bathe. One of those functional states may be readiness to alter connectivity in response to information flow, a function consistent with the idea of modulation of memory. ● Another explanation is based on the neurophysiological responses to some neurotransmitters involved in enhancement of memory. An example here is that the iontophoretic application of low levels of norepinephrine, serotonin, or acetylcholine can enhance both the postsynaptic excitation and inhibition produced by glutamate and GABA, respectively. Lecture 12 Neuroendocrine modulation of plasticity and memory Epinephrine (EPI) ● neurotransmitter (released by adrenal glands into the blood, does not reach brain) ○ used for memory enhancement (acts as a second messenger) ○ creates more glucose in the peripheral body: increases blood glucose levels→ glucose enters brain to reg. memory ■ glucose follows the pattern of the inverted U of learning → tested in avoidance training : ● The recent findings involving astrocytes in this mechanism suggest that activation involves glucose transport first into astrocytes, generating lactate from glycogen, which can then shuttle to neurons to meet energy demands of cognitive functions YerkesDodson law Empirical relationship between arousal and performance ( stress and memory) ● Relationship between performance and arousal (Inverted U) ● medium shock intensity is best for learning rather than low or high ● Increased arousal can improve performance to a certain degree, when arousal becomes excessive performance diminishes. ○ The simpler the task the better performance with high amounts of stress ○ The more difficult the task the more important of the middle amount of stress → Stress is not good for spatial memory aka Place response stress hinders Glucose in the brain: To determine one uses microdialysis ● extracellular glucose concentration is determined by zeroflux: ○ During microdialysis, at least 4 different concentrations of analyte are used, state where the the rate of neurotransmitter leaving the probe is equal to the rate entering Conclusions: ● Glucose enhances spontaneous alternation and spatial memory in rats ● Maze testing depletes glucose in the hippocampus of rats Glycogenolysis and memory: Breakdown of glycogen and converted to glucose Provides source of energy when demand is high Astrocytes store glycogen DAB blocks the breakdown of glycogen to lactate Lactate and Memory: lactate drug→ inverted U response curve adding 4cin blocks the uptake of glycogen to the neuron by inhibiting MCT2 activity DAB blocks the breakdown of glycogen Monocarboxylate transporter: Transporter that takes lactate from astrocyte and brings it to the neuron MCT1 brings lactate out of astrocyte, MCT2 allows uptake of lactate into neuron 4cin inhibits MCT2 activity Lecture 13 Neurochemistry of memory : Neurotransmitters/modulators NE, ACh The glucose enables Ach to be released more in hippocampus and enhances memory. In normal untreated rats, the normal amount of glucose, doesn’t increase the amount of ach being released. NE as a modulator (neurophysiological evidence): at baseline you have 5 cells firing, if you add NE doesn’t change= NO effect ● Excitatory: NE + Glutamate = MANY CELLS FIRING ● Inhibitory :NE + GABA = Few Cells firing → Highly dependent on the neurotransmitter its paired with Electron Microscopy: testing unique synaptic activity of NE ○ NE lacks receptors at post synapse (release site) ○ compared to a classic synapse which has 100% postsynaptic density → difference in densities suggests NE is a modulator ● These brain processes include augmentation of neurotransmitter release and of energy metabolism, the latter apparently including a key role for astrocytic glycogen. In addition to up and downregulation of learning and memory in general, physiological concomitants of emotion and arousal can also switch the neural system that controls learning at a particular time, at once improving some attributes of learning and impairing others in a manner that results in a change in the strategy used to solve a problem→ stress or DAB injection ● Physiological concomitants of emotion modulate memory. At a physiological level, emotional level, and memory are related in an invertedU manner. Moderate arousal enhances memory and very high arousal impairs memory. In this way, emotions can be either good or bad factors for memory processing. The bases for these relationships appear to be found through a biology that cross many systems, in particular the adrenal gland, liver, blood, and brain. It is worth noting that there is now extensive research on humans confirming the main effects of glucose on memory (Gold, 2001; Messier, 2004; Smith et al., 2011), although differences across species are very likely to emerge with further research. The up and downregulation of memory processing by physiological responses to emotion also has another dimension in shifting the strategy used to solve a problem. Evidence in rats suggests that high emotion shifts rats away from place learning strategies and toward response learning strategies. In terms of associated neural systems, the shift appears to be from hippocampus to striatum control over learning strategy. HPLC High Performance Liquid Chromatography ● Heat creates shorter wavelength and higher frequency ● Cold creates longer wavelength and smaller frequency Lecture 14 Brain Metabolism: Astrocytes ASTROCYTIC REGULATION OF MEMORY PROCESSING VIA GLYCOGEN Glycogen is found in astrocytes but not neurons Astrocyte: a starshaped glial cell of the central nervous system. Astrocyte → glycogen (glycolosis)→glucose → lactate → pyruvate neuron DRUGS 1) DAB 2) 4 Cin 3) MCT (monocaroxylate transporter) 1= transporter, 2= uptake into neuron a) can see if lactate improves memory b) blocks trasnporter from getting to neurons DAB ● 1 hr ● 24 hr ○ time memory tested after test ○ 1 hr after NO affect on DAB ■ DAB affects LTM ■ impaires LTM not STM 24 hr large affect on DAB impairs LTM (DAB drug that increases forgetting) 4 CIN inhibits MCT 2 not important for memory/plasticity Astrocytes and Memory: astrocytes are glial cells found in the brain capture glucose turn into glycogen ● activated by neurotransmitters glycogen is found in astrocytes helps produce lactate for energy use by the neurons during memory enhancement stores glycogen breaks down glycogen to lactate glycogen is better because it won’t diffuse in as much to explode Diagram?????? Biosensor used for lactate measurements:The biosensor contains a layer of lactate oxidase, which selectively breaks down lactate. The hydrogen peroxide produced is measured via electron transfer to a platinum wire in the probe. Glucose can be made from lactate. Glucose is a monosaccharide Glycogen is a disaccharide SPONTANEOUS ALTERNATION TESTING ● keep going to least visited arm on 4 arm maze ● task takes 20 minutes ● all entries were recorded and scored as an alternation if rat visited all 4 arms within 5 choices ○ RESULTS glucose decreases , lactate increases ○ lactate precedes the glucose ■ lactate improves memory ■ lactate drug → inverted U response curve ■ block glycogen breakdown Lecture 15 Integrative physiology of modulation: Aging and memory Lecture 16Protein Synthesis 1 ● Memory Formation: ○ protein synthesis independent (shortterm memory) ○ protein synthesis dependent (longterm memory) ○ phases of memory consolidation. ● a CNS manipulation that attenuates amnesia may be unrelated to the primary effects of the amnestic agent. For example, Flood et al., (1977) found that amnesia induced by the protein synthesis inhibitor anisomycin was attenuated by either amphetamine, strychnine or picrotoxin ● An examination of the literature about the attenuation of protein synthesis inhibitor induced amnesia led to some surprising conclusions. First, puromycin amnesia is attenuated by treatment with saline in a manner that is time dependent to the puromycin treatment. It seems that puromycin somehow blocks the expression of memory. However, if this is true, then the massive inhibition of protein synthesis produced by puromycin is not a necessary or sufficient condition to prevent the formation of new memories. ● Therefore, other inhibitors of protein synthesis that are known to produce amnesia must necessarily have additional actions. It was proposed that protein synthesis inhibitors produce amnesia through their cumulative widespread effects on many neural and endocrine systems. Second, the amnesia produced by protein synthesis inhibitors is not very robust and is readily reversed by a wide variety of attenuating treatments. Third, the conclusion that the amnestic effects of protein synthesis inhibitors may not be related to inhibition of protein synthesis is best supported by several studies showing that agents that either attenuate or potentiate protein synthesisinduced amnesia do nothing to significantly alter the rate of protein synthesis in the CNS. Protein Synthesis: ● Transcriptiongenetic code (DNA) transcribed ( copied) on mRNA in cell nucleus ● Translation mRNA leaves molecules and travels to ribosomes in the cytoplasm where to coded info is translated into specific amino acid (polypeptide )sequences in a protein→ folded Memories after EXPERIENCES: ● Short Term Mem: vulnerable to disruption, active state has rapid decay ○ LTM is less vulnerable, inactive state and slow decay Challenges to prevailing models: ● 90+% PSI is required for memory impairments. ● PSIs do not impair memory for training with high footshock, for extinction training, olfactory memory. ● Can block amnesia / rescue memory with: ■ amphetamine clonidine ■ isoproterenol caffeine ■ nicotine naloxone ■ corticosterone AChE inhibitors ■ clenbuterol (βadrenergic agonist) ■ propranolol (βadrenergic antagonist) ● Can also block amnesia with: ○ peripheral adrenergic antagonists (block stress to PSI?) Conclusion from HC + Amygdala studies: ● Protein synthesis inhibition can impair both short and longterm memory ● A function of brain system more than treatment → Particularly when viewed in the context of the rapidity (within minutes) with which brain structure can change, the need for the three Ts transcription and translation and transport – to cause these changes seems unlikely. Lecture 17Protein Synthesis 2 Lecture 18 Krebs Cycle ● The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. Increases in the concentration of either calcium or cAMP can trigger the phosphorylation and activation of CREB. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory . Here we review the key features of CREBdependent transcription, as well as the involvement of CREB in memory formation. Evidence from Aplysia,Drosophila, mice, and rats shows that CREBdependent transcription is required for the cellular events underlying longterm but not shortterm memory. While the work inAplysia and Drosophila only involved CREB function in very simple forms of conditioning, genetic and pharmacological studies in mice and rats demonstrate that CREB is required for a variety of complex forms of memory, including spatial and social learning, thus indicating that CREB may be a universal modulator of processes required for memory formation. Epinephrine enables memory in KO mice: ● CREB deficiency impairs water maze learning, which is predominantly attributable to a marked increase in wall hugging (thigmotaxis). A, Water maze learning in Creb CamKCre7 was indistinguishable from wildtype littermates. B, Creb NesCre mice displayed a significantly increased swim path length. C, Marked reduction of CREB in the forebrain did not impair spatial memory. D, Apparent deficits of spatial memory in Creb NesCre mice during probe trial 1. E, Pooling of four Creb mutant strains (Creb CamKCre7, Creb NesCre, Creb, and Creb comp) and three wildtype strains, respectively, contrasts the performance deficits of CREBdeficient mutants with their littermate controls. F, In mutant strains, the percentage of thigmotaxis is markedly increased. Twoway ANOVA with repeated measures with days 1–14 and genotype (mutant and wild type) as factors was used for the analysis of the values depicted in Figure 4. The p values represent the genotype effect. ● Intra Amygdala Injections of CREB Antisense impair memory: ○ depressed CREB in antiese CREB CONCLUSIONS ● Suppressed trainingrelated release of NE after CREB antisense treatment may contribute to memory impairments, suggesting mechanisms beyond inhibition of protein synthesis. ● Possible alternative mechanisms are also suggested by EPI reversal of memory loss in CREB KO mice. ● More generally, the findings suggest a possible role of CREB in local circuit dynamics that may modulate memory formation. Action potential: The system is set with potential energy to accomplish its goal. The need for energy is for replenishment of ions after an action potential. Memory : The system is set with potential energy to change connections. A need for protein synthesis is to replenish proteins after memory formation. Lecture 19 LTP 1 Longterm potentiation is an enduring form of synaptic plasticity mechanism of memory ● LTP can be studied in intact awake rats and mice, in anesthetized rats and mice, and in brain slice preparations taken from rats and mice. ● In each case, electrical stimulation is (test stimulus) can be delivered to afferent fibers and the resultant summated / field EPSP can be recorded in the postsynaptic neuron. ● Delivering a brief 1sec duration train of high frequency (e.g. 100 Hz) stimuli (i.e., the tetanus) to the afferent nerve produces two types of enhancement in the postsynaptic neuron. First, there is a transient facilitation called posttetanic potentiation (PTP) that dies away after several minutes. Second, following the PTP is an enduring enhancement of the EPSP called LTP, which can last for hours to days to months. Synaptic Integration: Temporal vs Spatial Temporal: ● additive effect produced by many EPSPs that have been generated on the same synapse by a series of high frequency Action Potentials on the presynaptic neuron Spatial: ● additive effect produced by many EPSPs that have been generated at many different synapses on the same postsynaptic neuron at the same time Lecture 20 LTP 2 EPSP’s:Single Neuron Spike (AP) vs Population Spike Standard Intraneural EPSP = recording from one cell FIeld ( population) EPSP = recording extracellularly from a population of cells Evoked Response with LTP: ● Before LTP= small pop spike and EPSP spike ● After LTP= field EPSP & no pop spike → Pop spike is tangent line of after LTP (height or amp.) & field EPSP is the slope of AP Neural Silencing: → normal vs silenced wavelength activity ● brain suppressed spontaneous and evoked local potentials ● injections of PSI anisomycin cause this inactivation Longterm potentiation (LTP): a candidate cellular mechanism of memory ● Some properties of learned behaviors: ○ Experiencedependent ○ Input specific ○ Rapid induction ○ Longlasting ● Some properties of LTP: ○ LTP is experiencedependent ■ Need stimulation to induce a large change in synaptic strength ○ LTP is input specific ■ Only the conditioned (tetanized) pathway is potentiated ○ LTP is induced rapidly ■ Conditioning stimulation needed for only a few seconds ○ LTP is longlasting ■ Can last hours to days Lecture 21 LTP 2 The phenomenon: synaptic plasticity (4/6) & Mini Quiz 1 Tisynaptic Flow of Info through the Hippocampal:Perforant path: ● Dentate Gyrus →(mossy fibers) → CA3 → (Schaffer Collateral) →CA1 Experimental design: Simulation vs Recording in electrodes ● Stimulate a bundle ofpresynaptic axons: hippocampal perforant path ○ mossy fibers and schaffers collateral ● Record extracellular electrode to measure monosynaptic EPSP ○ dentate gyrus, CA3, CA1 ● Record population response before and after high frequency stimulation ● Increase in population response indicates potentiation → Hippocampal slice preparations have supported and extended the findings of Bliss and Lomo Lecture 22 LTP 3 Mechanisms of the change (4/8) & Mini Quiz 2 stuff on mice: reaching tasks pop spike how poerful the response is SPECIFICITY LTP is input SPECIFIC ● input HIGH freq to input 1 ● only input 1 is activated ● input 2 NOTHING happens ○ LTP is only in #1 ASSOCIATIVITY ● stimulate 1 w/ high freq ● stimulate 2 w/ little freq ○ BOTH are activated TEMPORAL SUMMATION associatvity inputs are activated at same time SPATIAL SUMMATION specifictiy inputs activated separately Inhibitory avoidance trained animals ● increase in response ● LTP ● stimulated aftger shcoked ● shock at baseline (100%) ○ trained animals show a > provoked response than control animals ○ HIGH FREQ RESPONSE ■ animals trained NO increase response ■ animals controlled increase response OCCLUSION behavior induced LTP masks ability to produce LTP in other means Lecture 23 4/1 LTP III Lecture 24 4/20 Changing brain maps I Brain maps basics: Plasticity of sensory and motor systems I Learning Induced LTP in Neocortex ( M1) Saturation: ● maximal expression of LTD ( learning ) in the entire population of relevant synapses ○ all plasticity used up in learning and not enough to undergo LTP ● LTP & LTD( learning ) compete for the finite amount of plasticity available. This task shows that learning a task before performing induces LTP associated with learning and causes deficits in LTP in the long term. If you induce LTP before learning this causes learning deficits which shows overlap in systems. Behavioral Memories: ● inhibitory control freeze task with control and amniomyscin ● trained to get shock with tone ● memory recorded if it freezes when given shock at 3 different time intervals (1,6, 24 hours post training) ● shows effects of learning and decay in memory consolation because: ○ extinction, cell saturation, neural signaling, PSI theory Lecture 25 4/22 Changing brain maps II Plasticity of sensory and motor systems & Plasticity of brain anatomy I Weinberger Review: ● Learning and memory involve the storage of specific sensory experiences. However, until recently the idea that the primary sensory cortices could store specific memory traces had received little attention. Converging evidence obtained using techniques from sensory physiology and the neurobiology of learning and memory supports the idea that the primary auditory cortex acquires and retains specific memory traces about the behavioural significance of selected sounds. The cholinergic system of the nucleus basalis, when properly engaged, is sufficient to induce both specific memory traces and specific behavioural memory. A contemporary view of the primary auditory cortex should incorporate its mnemonic and other cognitive functions. Brandon & Cross: ● studied honeybees using rapid Golgi method to show that dendrite spines on calycal interneurons had shorter stems due to head enlargement in bees with greater cumulative flight a one trial place learning event ● newly emerged bees were reared in a small broodless hive with a virgin queen and allowed to take their first orientation flight at 6 and 8 days of age ● spine profiles of 5 flyers and 5 nonflyers were traced in large scale using light microscopy and a modified camera lucida ● overall spine length and stem length were measured on these tracings using a digitizing tablet. ● additional measurements of maximum spine head width, profile areas, and perimeters were made using computer image analysis. ● Examining group differences in spine stem length as a function of overall spine length, our results revealed a clear association between rapid spine stem shortening and the first orientation flight lasting several minutes ● this effect was restricted to only the long spines ● flightinduced stem shortening was accompanied by elongated swelling of the spine head without an appreciable expansion of the spine perimeter Barack, ismail, Robinson→ Stimulating Muscarinic Receptors ● Honey bees begin life working in the hive. At 3 weeks of age, they shift to visiting flowers to forage for pollen and nectar. Foraging is a complex task associated with enlargement of the mushroom bodies, a brain region important in insects for certain forms of learning and memory. We report here that foraging bees had a larger volume of mushroom body neuropil than did age matched bees confined to the hive. This result indicates that direct experience of the world outside the hive causes mushroom body neuropil growth in bees. We also show that oral treatment of caged bees with pilocarpine, a muscarinic agonist, induced an increase in the volume of the neuropil similar to that seen after a week of foraging experience. Effects of pilocarpine were blocked by scopolamine, a muscarinic antagonist. Our results suggest that signaling in cholinergic pathways couples experience to structural brain plasticity. Roszenberg Changes in Cerebral due to Negative Training ● Negative Changes may also store information in the Nervous System: ● cerebral changes induced by experience Lecture 26 4 /27Plasticity of brain anatomy 2 Dysgenesis ● Golgi studies reveal abnormally long, thin spines and the absence of short, thick spines on dendrites of cortical neurons in retarded children with normal karyotypes. The degree of dendritic spine loss and abnormality appears to be related to age and the severity of developmental retardation. Dendritic spine "dysgenesis" is a common feature of the microstructural pathology that occurs in profound mental retardation of unknown etiology. ● This study demonstrates two types of dendritic spine abnormalities in retarded children with normal karyotypes: dendritic spine loss and the presence of very long, thin spines that resemble the developing spines of primitive neurons (2). The functional significance of these abnormalities is not known. However, it is reasonable to expect that spine loss and alterations in dendritic spine geometry (7) exert significant effects on integrative operations of dendritic systems as receptor surfaces for synaptic inputs to cortical neurons (1, 8). The emphasis here on dendritic spine "dysgenesis," which implies defective development, as a common feature of the microstructural pathology in profound mental retardation affirms the importance of axodendritic synaptic dysfunction in many developmental disorde Simon Levay: ● The anterior hypothalamus of the brain participates in the regulation of maletypical sexual behavior. The volumes of four cell groups in this region [interstitial nuclei of the anterior hypothalamus (INAH) 1, 2, 3, and 4] were measured in postmortem tissue from three subject groups: women, men who were presumed to be heterosexual, and homosexual men. No differences were found between the groups in the volumes of INAH 1, 2, or 4. As has been reported previously, INAH 3 was more than twice as large in the heterosexual men as in the women. It was also, however, more than twice as large in the heterosexual men as in the homosexual men. This finding indicates that INAH is dimorphic with sexual orientation, at least in men, and suggests that sexual orientation has a biological substrate ● The discovery that a nucleus differs in size between heterosexual and homosexual men illustrates that sexual orientation in humans is amenable to study at the biological level, and this discovery opens the door to studies of neurotransmitters or receptors that might be involved in regulating this aspect of personality. Further interpretation of the results of this study must be considered speculative. In particular, the results do not allow one to decide if the size of INAH 3 in an individual is the cause or consequence of that individual's sexual orientation, or if the size of INAH 3 and sexual orientation covary under the influence of some third, unidentified variable. In rats, however, the sexual dimorphism of the apparently comparable hypothalamic nucleus, the sexually dimorphic nucleus of the preoptic area (SDNPOA) (16), arises as a consequence of the dependence of its constituent neurons on circulating androgen during a perinatal sensitive period (17). After this period, even extreme interventions, such as castration, have little effect on the size of the nucleus. Furthermore, even among normal male rats there is a variability in the size of SDNPOA that is strongly correlated with the amount of maletypical sexual behavior shown by the animals (18). Although the validity of the comparison between species is uncertain, it seems more likely that in humans, too, the size of INAH 3 is established early in life and later influences sexual behavior than that the reverse is true. In this connection it would be of interest to establish when the neurons composing INAH 3 are generated and when they differentiate into a dimorphic nucleus. Negative Changes may also store information in the Nervous System: ● cerebral changes induced by experience Exam 1: Exam 2: Page 1 Page 2 Page 3 Page 4 Page 5 Page 6 Page 7 Exam 3: Exam 3 Key Articles Explained above: READING ARTICLE: “Coordination of multiple memory systems” Paul E. Gold* ● ABSTRACT: On the basis of lesions of different brain areas, several neural systems appear to be important for processing information regarding different types of learning and memory. This paper examines the development of pharmacological and neurochemical approaches to multiple memory systems from past studies of modulation of memory formation. The findings suggest that peripheral neuroendocrine mechanisms that regulate memory processing may target their actions toward those neural systems most engaged in the processing of learning and memory. In addition, measurements of acetylcholine release in different memory systems reveals extensive interactions between memory systems, some cooperative and some competitive. These results imply that many neural systems, often characterized as relatively independent, may in fact interact extensively, blurring the dependencies of different memory tasks on specific neural systems ● CONCLUSION: The findings reviewed here show multiple examples of interactions between neural systems. First, the interactions are not only competitive but can also be cooperative. These relationships can be nonreciprocal, with the hippocampus apparently competing with the amygdala and the amygdala cooperating with the hippocampus during learning. While there are clearly important task distinctions to be made in ascribing functions to different memory systems, the findings of extensive interactions described here and in other papers in this issue make murky the extent to which the systems can be considered to be independent memory systems. For example, while place and response learning appear to be dependent on the functional integrity of the hippocampus and striatum, respectively, each is also dependent on the function of the other system in the sense that activation of the alternative system impairs learning. While much of the field of multiple memory systems has focused on positive dependencies, the role of negative dependencies need not be less important. ● The interactions across systems are not necessarily direct in the sense that upregulation of one brain area downregulates another. In a retrospective analysis of ACh release in the hippocampus and striatum across studies, we found no evidence for a negative correlation(unpublished findings) indicating that, at least with this neural marker, a reciprocal relationship is not evident. One possibility is that the products of the processing in each system are collected by another, undefined, brain area to control output of learned responses. This logical possibility does not have direct empirical support, and tests of systems with an output function of this sort are needed “Modulation of Multiple Memory Systems: From Neurotransmitters to Metabolic Substrates” Paul Gold & Donna Korol ● ABSTRACT: This article reviews evidence showing that neurochemical modulators can regulate the relative participation of the hippocampus and striatum in learning and memory tasks. For example, relative release of acetylcholine increases in the hippocampus and striatum reflects the relative engagement of these brain systems during learning of place and response tasks. Acetylcholine release is regulated in part by available brain glucose levels, which themselves are dynamically modified during learning. Recent findings suggest that glucose acts through astrocytes to deliver lactate to neurons. Brain glycogen is contained in astrocytes and provides a capacity to deliver energy substrates to neurons when needed, a need that can be generated by training on tasks that target hippocampal and striatal processing mechanisms. These results integrate an increase in blood glucose after epinephrine release from the adrenal medulla with provision of brain energy substrates, including lactate released from astrocytes. Together, the availability of peripheral and central energy substrates regulate the processing of learning and memory within and across multiple neural systems. Dysfunctions of the physiological steps that modulate memory—from hormones to neurotransmitters to metabolic substrates—may contribute importantly to some of the cognitive impairments seen during normal aging and during neurodegenerative diseases. ● CONCLUSION: The research described here provides evidence for neurochemical mechanisms that control the balance between multiple learning and memory systems. These mechanisms are subject to pharmacological control, as evidenced by the effects of direct brain injections of glucose into specific brain regions; similar results are also seen with neurotransmitter receptor agonists and antagonists. For acetylcholine, it appears that both hippocampal and striatal tasks result in increases in release of the neurotransmitter, but that the patterns of release change as rats progress through different stages of training reflecting changes in the use of different cognitive strategies and attributes during training. This review also raises a potentially important role for astrocytes in balancing the relat
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