NRSC 4032 Ch9-14

14. What role does the vagus nerve play in memory modulation?

a. Allows signal of arousing event to be transmitted to the brain via its connections and ultimate release of NE

11. For what purpose would you use the antisense methodology?

a. Eliminate that protein from being transcribed?

3. What is the significance of the PKM KO mouse?

a. Knockout mice can aquire and maintain fear memories and place learning memories b. PKMz KO mice learn and remember c. Interfering with PKMz erases spatial memory

5. What, in general, does the antisense methodology accomplish?

a. Protein will not be available to target transcription of new mRNAs needed to produce the enduring memory

18. The study of what three proteins has provided evidence that consolidation takes place in multiple rounds of protein synthesis? Can you provide experimental examples?

?

5. What is the difference between NMDA receptors composed of NR1-NR2A versus NR1-NR2B subtypes?

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formation of a memory trace

The formation of a memory trace begins when a behavioral experience activates a neuronal ensemble that represents the experience. The formation of a memory trace begins when a BEHAVIORAL EXPERIENCE activates a set of WEAKLY CONNECTED neurons.

2. Describe the composition of NMDA receptors.

a. 4 subunits b. All functional NMDA receptors have GluN1 c. Variety of GluN2 (A-D) i. GluN2A and B d. Each receptor has four subunits, and they are some combination of the two classes GluN1 and GluN2.

22. Describe how the subunit composition of both AMPA and NMDA receptors affects working and reference memory.

a. AMPA i. GluA1 required for early phase LTP, not developing phase (GluA2) enduring can be established ind. Of GluA1 ii. GluA1 knockout mice can display an enduring LTP, but not the rapidly formed early phase. They can learn and remember the reference memory component, but impaired working memory. 1. Implies GluA1 receptors are critical for WORKING MEMORY b. NMDA i. Receptors composed of GluN1 and GluN2A required for working memory, not reference memory 1. No evidence if any combo needed to support reference memory ii. GLUN2A REQUIRED FOR WORKING MEMORY, not reference c. Both i. Subunit comp of both is critical for working memory ii. Depends on insertion of GluA1, which depends on NMDA receptors composed of GluN1 and GluN2A iii. Neither enduring LTP or reference memory requires GluA1

7. Why is the fact that. PKM KO mice can maintain memories not conclusive evidence against the hypothesis that PKM is a memory maintenance molecule.

a. Does not reveal what the brain can do in the absence of the substrate

4. What are some of the methods neurobiologists use to influence brain function? And to

a. Experimentally damaging to a particular region of the brain b. Injecting drugs in the brain designed to influence some aspect on neural function c. Genetic engineering(modify DNA) to increase or decrease the expression of some potential memory molecule

13. When should you worry about the ceiling effect vs the floor effect?

a. If response measure is at the max, there is no way to see influence of some other manipulation b. Performance measure is too low to be further reduced by the drugs c. When a treatment is hypothesized to impair the memory processes that produce avoidance behavior, but the performance measure was too low to be further reduced by the drug.

25. What is the consolidation window?

a. Multiple windows of vulnerability for consolidation processes

16. Describe Tonegawa's experiment with the CA1KO mouse. What is its significance?

a. Tonegawa deleted the GluN1 subunit in pyramidal cells in the CA1 field of the mouse hippocampus.

21. What is the radial arm maze methodology?

a. Used to study working and reference memory b. Only 4/8 arms baited each time c. Rat has to learn what are never baited (r mem) and remember it previously visited ( w mem) d. (1) Working memory requires the animal to remember which arm was already visited; and (2) Reference memory requires the animal to discriminate between the arms always baited and the arms never baited.

BBB: E and vagus connection

c. When E administered to anesthetized rats, activates vegal nerve i. Outcome prevented by beta adrenergic receptor antagonist sotalol d. Result supports that E binds to B adrenergic receptors on vacal nerve e. E in periphery increases firing rate of neurons in LC, and temporary inactivation of neurons in the NTS reduces mem enhancement by peripheral injection of E f. Stimulating vagus nerve following inhibitory avaoidance training can enhance memory g. Rats have to both explore their environment and then receive electrical shock for NE to be released in the amygdala h. Following inhibitory avoidance training, NE injected into the basolateral amygdala should either enhance or impair retention performance, depending on dose and time

3. What is a behaviorally induced genomic cascade?

d. A behavioral experience, such as inhibitory avoidance training, initiates a genomic signaling cascade that results in new plasticity products needed to consolidate the memory for the experience

17. What is the evidence for the neuro-hormonal circuit?

d. Disrupting any component of this neuro-hormonal circuit will prevent arousal from enhancing memory. e. When E is administered to rats, activates vagus nerve i. Outcome prevented by sotalol f. E in periphery increases firing rates of neurons in the LC g. Temporary inactivation of neurons in NTS reduces memory enhancement by a peripheral injection of E h. Results indicate E in peripher activates LC through NTS

b. Epinephrine in the liver-glucose connection: glucose modulates memory

i. A systemic injections of either epinephrine or glucose influence memory strength in a dose-dependent manner. ii. These data support the view that epinephrine modulates memory by binding to adrenergic receptors on the liver cells causing them to release glucose

1. What is the basic paradigm used in all studies of learning and memory?

i. Experience observable->memory trace inferred->behavioral change observable->window to the memory trace(->memory trace)

d. CREB selection of neurons that participate in memory trace

i. Herpes simlex viral vector infects some neurons in the LA with CREB ii. These neurons that now overexpress CREB are preferentially selected to become part of the engram that supports fear memory iii. Diptheria neurotoxin selectively kills neurons that overexpress CREB iv. Results of fear conditioning experiment revealed that the diptheria treatment that selectively killed neurons overexpressing CREB also erased fear memory v. Results implicate thatL 1. Neurons in LA compete to participate in the neuron ensemble that supports the fear memory 2. Neurons expressing high levels of CREB at the time of fear conditioning win the competition a. Neurons that overexpressed CREB were preferentially selected to become part of the neural ensemble supporting the fear memory

CREB antisense

i. Rats normal 30 minutes after ii. Impaired 3 days after training iii. Impaired LTM for place learning and morris water escape task iv. Does not affect STM v. Antisense group had longer escape latenies when retention interval was 3 days

6. Defend this assertion. PKMis a memory maintenance molecule.

i. Substitute kinases can be targets of ZIP

1. Describe the memory modulation framework. What is the role of the amygdala, the hippocampus, and the adrenal gland?

a. A behavioral experience can have 2 independent effects: i. Activate specific sets of neurons that represent and store contents of the experience ii. Activate hormonal and other neural sustems that can influence systems that store memory b. Hormonal and other neural systems are called memory modulators. i. Not part of the storage system, but they can influence the synapses that store the memory c. Memory modulators have a time limited role and influence only the storage of very recently acquired memories. Operate during a period of time shortly after the behavioral experience when the trace is being consolidated d. Neural systems that modulate memory strength are not necessary for the retrieval of the memory

14. Given what you know about mechanisms of synaptic plasticity how would you explain short-term memory?

a. A behavioral experience that produces a memory is likely to result in more phosphorylated cofilin and more autophosphorylated CaMKII. b. The autophosphorylation of camk2 may be critical for the rapid formation of a memory but other processes can compensate for this contribution when multiple training trials occur. c. Is it reasonable to expect that behavioral experiences that produce memories would engage the LIMK signaling pathway? i. Yes, because actin polymerization is necessary for synaptic changes in LTP.

8. Discuss the rationale for the AMPA receptor trafficking experiments by Malinow's group (i.e., the Rumpel et al. experiments).

a. Accepted that LTP=result of induction of GluA1 receptors into the spines b. One expect that if mem formation depends on synaptic changes that support LTP, then behavioral experiences that produce memories should also traffic additional GluA1 AMPA into spines c. Experiment Provided evidence for how LTP drive GluA1 AMPA receptors into spines. d. Second experiment AMPA trafficking: i. If GluA1 plays critical role in fear memory, then trafficking this receptor into spineprevented, fear mem should be weak e. Malinow's experiments showed that the memory for the fear experience, as measured by the rat's FREEZING RESPONSEdepends on trafficking AMPA receptors with functional GluA1 subunits into the membrane. f. 2 STRATEGIES TO PROVE THAT FEAR CONDITIONING DRIVES AMPA receptors into amygdala neuron synapses: i. 1. In one case he created identifiable GluA1 receptors and infected neurons in the amygdala with these receptors to show that fear conditioning would drive them into synapses. ii. 2. He created dummy receptors to compete with endogenous receptors and showed that their presence impaired fear conditioning. g. After the training, rats in the paired condition had more GluA1 receptors trafficked into the plasma membrane than rats in the unpaired condition. i. FEAR CONDITIONING DRIVES AMPA RECEPTORS INTO THE SYNAPSE h. Complimentary approach: if trafficking of AMPA receptors is important should be able to demonstrate 2 things: behavior traffics AMPA receptors, and that those trafficked receptors are functionsl (expression of memory depends on trafficking

23. What is the evidence that new protein synthesis for consolidation happens in waves?

a. Agents that prevent transcription and translation have time-limited effects on memory b. In intact animal, first wave occurs noncontinuously and in waves

12. How are amphetamine and lidocaine used to study the amygdala?

a. Amphetamine i. Stimulant that improved retention performance ii. (A) Injecting the stimulant amphetamine into the amygdala following training on the place-learning version of the Morris water-escape task improved retention performance. b. Lidocane i. Drug that temporarily suppresses neuronal activity ii. Memory retention impaired iii. Lidocaine injected into the BLA prevents memory modulation iv. Injection in BLA should Reduce the level of Arc protein in the hippocampus and impair memory retention demonstrated by decreased inhibitory avoidance

7. Which memory tasks can be learned and remembered even with the amygdala removed? Why is that important?

a. Amygdala facilitates the storage of memories, but not needed to retain memory b. Evidence amygdala facilitates storage of memories but not needed to retain: i. both the place-learning and visible-platform versions of the Morris water-escape task can be learned and remembered even when the amygdala is significantly damaged, however, when a stimulant drug is injected into the amygdala following training, retention performance on both versions of the task is enhanced.

10. What are the three immediate early genes targeted by CREB?

a. Arc b. BDNF c. C/EBPb

20. What is the evidence that Arc is important for LTM?

a. Arc antisense ODN impairs LTM but not STM b. Impaired memory for fear conditioning experience when the retention interval was 24 hours, not 3

17. What changes in NMDA receptor composition are observed during neural development? What are the differences in the properties of the different subunits?

a. As the nervous system develops, the GluN2B subunits tend to be replaced by GluN2A subunits. b. When GluN2B subunits dominate, it is easier to induce LTP than when GluA2 subunits dominate.

13. CaMK2 and fear memories

a. Autophosphorylation is critical for rapid formation of a fear memory but not essential for memories produced with multiple training trials b. In an experiment, mice genetically engineered to impair autophosphorylation of CaMK2 (T286Amice) and controle mice received 1,3,or5 pairings of a tone and shock c. Control mice acquired fear to the context and to the tone after only 1 pairing d. Defective mice required several pairings e. Fear conditioning produces increased phosphorylated CaMK2 in dendritic spines in the amygdala. Rats that received paired presentations of a tone and shock have more particles of phosphorylated CaMK2 in spines than control with no shock/unpaired presentations f. Drug KN-62 inhibits phosphorylation i. Impairs both contextual and tone

24. What are the three waves of consolidation? What is accomplished in each one?

a. BDNF-mTOR pCREB i. First wave occurs during first hour following training ii. Involves local translation of new protein regulated by BDNF-mTOR signaling pathway iii. During initial period, genomic signaling acgtivated to phosphorylate CREB to translate new BDNF and Arc for next consolidation b. pCREB BDNF-mTOR Arc i. Second wave: In 3 hours, new round of consolidation takes place and persists for about 8-9 hours ii. Both waves dependent on consolidation are dependent on BDNF-mTOR pathway c. C/EBPb-IGF2 i. Third wave depends on transcription factor C/EBPb and its gene target IGF-2. 1. Antisense to either impairs memory even when it is infused 24 hours following training 2. Third wave active for 24 hours d. Observations indicate consolidation processes operate for at least 24 hours and within this there are multiple windows of vulnerability

8. What is propranolol?

a. Beta adrenergic receptor antagonist b. Injection in BLA should attenuate memory resulting from an arousing behavioral experience

9. Why is propranolol used in memory modulation experiments?

a. Blocks binding of NE to stimulate fear i. Injection of NE into amygdala following place learning enhanced rats retention of the platform location, but when propranol was injected, retention was impaired ii. NE injected into the amygdala following inhibitory avoidance training with a weak shock enhanced retention performance iii. Pro injected in the amygdala following inhibitory avoidance training with strong shock impaired retention

15. What are the conditioned response, the unconditioned stimulus, and the unconditioned stimulus in a fear conditioning?

a. CR=freezing b. CS= auditory stimulus c. US= shock

7. Describe the effects from CREB deletion,

a. CREB deletion i. Normal fear conditioning to short retention interval ii. Impaired long and MWM 1. Need plasticity products transcribed by CREB

6. Describe the evidence that CREB can rescue long-term memory impairment.

a. CREB overexpression in lateral amygdala where memory is stored results in demonstrated LTM b. LTM was poor when ITI was 10sec compaired to 8 c. Injecting virus that expresses CREB into lateral amygdala prior to conditioning can eliminate the impaired LTM normally found when ITI is only 10 sec

10. Several sources of evidence indicate that the basolateral amygdala modulates memory storage. What are they?

a. Connected to many regions of the brain likely storage sites for different types of memories i. In position to influence/modulate storage processes in other regions of the brain b. (A) Injecting the stimulant amphetamine into the amygdala following training on the place-learning version of the Morris water-escape task improved retention performance. c. (B) Injecting the amphetamine following training on the visibleplatform task improved retention performance. (Short latency indicates better retention.) d. The hippocampus is thought to be a critical storage site for place learning and the caudate is thought to be critical for the visible-platform task. e. (A) An injection of lidocaine into the basolateral nucleus of the amygdala (BLA) following avoidance training impaired the retention of the inhibitory avoidance response. f. (B) Lidocaine had no effect when it was injected into the central nucleus (CE) of the amygdala. LA = lateral nucleus; BA = basal nucleus.

9. What is the role of transcription in establishing LTM?

a. Construction of long term memories depends on meolecular products resulting from transcription, which emerged from LTP studies b. Arc BDNF are transcribed in response to behavioral experiences that generate LLM c. C/EBPb targets expression of other mRNAs that become important after many hours of behavioral experience

3. How have genetic engineering approaches supported the hypothesis that NMDA receptors are critical to memory formation?

a. Delete or overexpress subunits b. Deletion i. GluN1 in pyramidal cells in CA1 ii. LTP not induced iii. LTP possible if stimulated performant path and recorded in dentate gyrus iv. CRITICAL FOR MEM RESULTS: 1. Knockout mice very impaired in platform task with aquiring mem for location, but able to learn to swim directly to visible 2. CA3 dletion necessary for one trial place learning but not for learning of location of platform in same spot for every trial c. GLuN1 subunits are absent in the CA1 region d. LTP cannot be induced in CA1 in slices e. Overexpression i. Overexpressed GluN2B, and mice showed enhanced LTP and memory formation f. Drugs are said to be "dirty," meaning they are not highly selective to the intended target and it is hard to control for the spread of the drug to other regions. Moreover, by using biotechnology to directly influence the genome, it is possible to modify or delete the gene for a particular protein or to transfer new genes into the genome.

13. How does epinephrine released in the blood cause the release of norepinephrine in the BLA?

a. E binds to adrenergic receptors on vagus nerve b. Vagus carries info about body to brain and synapses on brain stem region-solitary tract nucleus i. Releases Glu on neurons in NTS c. Neurons from NTS synapse on collection of neurons in the brain stem called locus coeruleur i. Releases glu to these neurons d. Neurons in LC project to distant brain regions (forebrain, hippocampus, and amygdala) e. When activated, neurons release NE onto target neurons f. Release of NE into BLA=key outcome of the vagus connection

6. Describe an experiment that supports the hypothesis that the hormone epinephrine modulates memory storage processes.

a. Epinephrine in neuro-hormonal circuit i. On training trial, rats received a mild shock when they crossed to the dark side of the apparatus ii. Compared to control rats injected with the saline vehicle, rats that were injected with a dose of E (that was calculated to mimic the level of E naturally released if they received a strong shock) displayed enhanced inhibitory avoidance iii. Enhancing effect of E was time dependent. It was more effective when it was given shortly after training trial iv. Rats injected with E, displayed enhanced inhibitory avoidance (as if given strong shock) v. Enhancing effect time dependent, more effective shortly after training trial

4. What are the effects of ZIP in the PKM KO mouse?

a. Erases memories b. There is no time window constraining the effects of ZIP c. ZIP targets PKMζ and other memory maintenance kinases d. ZIP might erase memories in PKMz KO mice because there are compensatory, redundant molecules for PKMZ that also ZIP targets e. BY applyting ZIP to the appropriate brain region, consolidated memory can be erased: Spatial memory, fear memory, inhibitory avoidance memory, instrumental response memory, object-location memory, taste-aversion memory

18. Define the following: escape latency, path length, probe trial, annulus crossings, quadrant search time.

a. Escape latency-time it takes to find platform b. Path length-the distance the rodent swims before it finds the platform c. Probe trial-platform removed and rodent searches i. Collects info about where it swims in absence of platform d. Annulus crossings-measure how many times during probe trial the animal crosses the place the platform is located compared to crosses in other quadrents e. Quadrant search time- pool divided in 4 quads. Platform in 1. Rodent that has stored a mem of location will spend less of search time in other quadrants compared to the one it is in

11. What evidence suggests that the amygdala modulates memory strength by regulating the translation of Arc?

a. Experimental design: i. Cannula implanted into the amygdala ii. Rats trained on the inhibitory avoidance tast iii. Rats injected with either clenbuterol (b adrenergic agonist) or lidocaine (which inactivates BLA neurons) iv. Rats either sacrificed or tested on the IA task v. Hippocampus brain tissue was sample for Arc protein b. Results: i. Lidocaine reduced level of Arc in the hippocampus and decreased inhibitory avoidance ii. Clenbuterol increased the level of Arc protein and enhanced inhibitory avoidance iii. Results suggest that the BLA might modulate memory by influencing the level of Arc protein in the hippocampus c. Activity in the BLA produced by inhibitiory avoidance training modulates the level of Arc protein in the hippocampus d. Level of Arc correlates with the strength of memory e. Amygdala signal enhances Arc protein and CaMK2 levels in another storage area for inhibitory avoidance memory f. Inactivating neurons in the BLA reduces memory and the expression of Arc and CaMK2

21. What is the evidence that the UPS is involved in memory consolidation?

a. Fear conditioning induces polyubiquitination in amygdala b. Proteasome inhibitor impairs cued and contextual fear conditioning c. Results show protein degradation is critical for consolidating long-term fear memories d. Protein degradation is important for long-term fear memories. (A) Fear conditioning (FC) induces polyubiquitination in the amygdala. This process is prevented by the NMDA antagonist ifrenprodil. (B) The proteasome inhibitor blactone (blac) impairs both cued and contextual fear conditioning. These results indicate that protein degradation is critical for consolidating long-term fear memories

19. What is the evidence that BDNF is important for memory consolidation?

a. First peak of BDNF is critical for memory expressed on both 1 and 7 retention tests b. Second peak required only to support the memory expressed on the 7 day retention test c. (B) Impairing BDNF function 1 hour after training with either the BDNF scavenger TrkB-IgG or the TrKB antagonist K252a impairs the fear response at both the 1-day and 7-day retention intervals. (C) In contrast, administering these treatments 9 hours after training impairs the fear response only on the 7-day retention test. The measure of fear was the fear-potentiated startle response. Rats startle more to a brief loud noise in the presence of a fear stimulus. These results indicate that the first peak of BDNF is critical for the memory expressed on both the 1- and 7-day retention tests. However, the second peak is required only to support the memory expressed on the 7-day retention test

7. Explain the concept of memory consolidation. What are consolidation processes? What is the consolidation period?

a. Following a learning experience, a memory is vulnerable to disruption. With the passage of time, resistance to memory disruption increases and the trace becomes more stable b. Term used to describe the change from vulnerable to less vulnerable i. Consolidation period is the time it takes to achieve this outcome

22. What is optogenetics? What are its benefits? Describe how it is used to excite or inhibit the neuron.

a. Genetic engeneering with optics b. Benefits i. Identify specific neurons and their contributions to specific brain functions ii. Light can control neurons with temp. and regional specificity needed to map out complex functional circuits of brain iii. allows scientist to control one type of cell without altering other types. c. Excite: channelrhodopsin i. Depolarization in response to blue light, activating the neurons ii. Open and close and conduct positive ions d. Inhibit: halorhodopsin i. Stimulated with green, conduct negatively charged cl ions and hyperpolarize neuron e. When activated by blue light, channelrhodopsins (channel proteins) could be stimulated to open and close with millisecond precision and conduct positive ions with the result of depolarizing the neuron. Halorhodopsins, when stimulated with green light, conduct negatively charged chloride ions and thereby hyperpolarize the neuron.

15. What is the composition of NMDA receptors? What subunit is always present in functional NMDA receptors?

a. GluN1 b. Receptors composed of GluN1 and GluN2A required for working memory, not reference memory i. No evidence if any combo needed to support reference memory

19. Describe Morris's experiment to study the effects of NMDA and AMPA receptors on memory acquisition and retrieval. What did he find?

a. He implanted a cannula to deliver the NMDA receptor antagonist APV into the ventricular system of a rat's brain where it would enter the cerebral spinal fluid. He was testing the hypothesis that the initial formation of a memory trace depends on the activation of NMDA receptors. b. Richard Morris was the first researcher to directly investigate the role of NMDA memory formation. c. To influence NMDA function, he i. Used a pharmacological approach ii. Infused APV into the brain iii. Tested rats in the space-learning swim task d. Implanted a cannula into a cerebral ventricle

2. What are memory modulators?

a. Hormonal and other neural systems that are not part of the storage system, but can influence synapses that store memory b. INFLUENCE STRENGTH OF THE MEMORY AND SYNAPSES THAT STORE MEMORIES c. Influence only the storage of very recently aquired memories

4. Describe the conceptual basis of Joe Tsien's experiments featuring Doogie mice.

a. Hypothesized GluN2B could improve memory based on the fact the subunits remain open longer and permit more calcium to enter the spine and induce LTP b. The Doogie mouse is genetically engineered to overexpress __GluN2b_______ subunits. c. The Doogie mouse was genetically engineered to overexpress GluN2B subunits in the cortex and the hippocampus. Doogie mice displayed enhanced LTP, enhanced memory formation, and superior performance in behavioral tests.

18. Describe the role of AMPA receptors in memory formation and retrieval.

a. Important for both b. "GluA1 subunits are required for the initial early phase of LTP but not for the later developing phase." i. This is true because, when stimulated by a stronger theta-burst protocol, slices from the GluA1 of KO mice display an enduring LTP equivalent to control mice, even though they do not display the early, short-lasting phase.

4. Summarize the evidence that CREB contributes to long-term memory.

a. Important to production of memory genes b. Kandels lab and Aplysia believed transcription factor CREB played a role for results i. Inhibition of transcription factors affects LTM c. Rusiko bourchouladze i. Genetically engineered mice to repress CREB ii. These mice displayed fear when tested 3 hours after training, not when tested 24 hours after iii. These results are consistent with the hypothesis that LTM, not STM, requires plasticity products transcribed by CREB

11. What are the three most prevalent Behavioral Test Methods for Studying Memory?

a. Inhibitory avoidance conditioning b. Fear conditioning c. Spatial learning in water-escape task

1. Describe the experiments with PKM by Yadin Dudai. What did he find?

a. Injected ZIP into insular cortex (storage site for taste aversion mems) b. Single injection erased memory c. Did not alter acquisition of a new taste aversion d. ZIP will erase taste aversion memories, when injected into the INSULAR CORTEX but not when injected into the HIPPOCAMPUS e. Also, infected neurons in insular cortex with lentivirus designed to transfect these neurons with a dominant negative gene with inative form of PKMz f. This mRNA would compete with functional g. Rats with virus had reduced taste aversion when tested 6 days later h. To determine if PKMζ could strengthen a weak memory, rats were trained with a taste-aversion protocol designed to produce a WEAK TASTE AVERSION i. Rats were trained with taste-aversion protocol designed to produce a weak taste aversion. Injecting LV into insular cortex 5 days prior enhanced memory-converted weak memory to a strong one j. Rats tested 9 days after training. Injecting PKMz 6 days after draining prevented normal forgetting

8. How would you defend this assertion? Some forgetting is the result of active molecular processes.

a. Interference theory- additional experiences overwrite/produce new mems that interferte with retrieval of preexisting mems i. Additional experiences overwriting existing memories or producing new memories that interfere with the retrieval of the older memories. b. Active decay theory- over time, molecular processes actively degrade the synaptic basis of unused memories

12. What evidence supports a role for CaMKII in memory formation?

a. LTP could not be induced in the knockout mice and they were severely impaired on visible platform and place learning water escape b. Knockout mouse can learn to swim to the visible platform, but not the location i. Do not selectively search the target quadrant

15. What is the locus coeruleus? How is it involved in memory modulation?

a. Locus coeruleus b. Collection of neurons that project to distant brain regions and release NE

7. Discuss some of the problems associated with pharmacological approaches to blocking NMDA receptors.

a. May mean there are other mechanisms that can produce memories when NMDA not functional b. Does not reveal what that component does in the normal brain

14. Systemic injections of anisomycin following training impair long-term memory but have no effect on short-term memory. What are the strong and weak conclusions you can draw from this outcome?

a. Memories can be retrieved from a short-term or long term memory trace b. 2 traces have different molecular requirements: long term trace requires new proteins synthesized in response to neural activity induced by training experience c. Blocking protein synthesis is not important, it must be blocked shortly after the behavioral experience

Ampakines

a. Modulate receptor channel function and enhance learning b. Ampakines bind to a site on AMPA receptors and increase the duration of the channel opening when glutamate also binds to the receptor. c. Cross the BBB d. Ampakines are neither agonists nor antagonists. e. When glutamate and ampakines both bind to the AMPA receptor the channel stays open longer

1. What is the pharmacological evidence supporting the idea that NMDA receptors are important in memory formation?

a. Morris Implanted cannula to deliver AVP where enter CSF b. Reasoned fluid would diffuse and occupy receptors throughout the brain c. Found that AVP prevented induction of LTP in dentage gyrus and impaired rats ability to learn location of the hidden platform d. Evidence NMDA culd also participate in initiation of memorhy trace

11. What is the role of NMDA and AMPA receptors in the acquisition and retrieval of memory? Describe evidence to support your answer.

a. NMDA i. Only critical for acquisition of memory b. AMPA i. Contribute to both retrieval and memory c. Evidence i. One trial memory test in arena with 2 landmarks 1. Had to remember location of food pellet ii. Learned to dig in sand with flavor pellots iii. Used AVP or CNQX injected into hippocampus either before acquisition or retrieval phase iv. AVP impairmed performance when injected before acquisition, not before retrieval v. CNQX critical for both

5. Given that the hormone epinephrine does not cross the blood-brain barrier, how can it influence amygdala function?

a. One path starts with E binding to receptors on the vagal nerve and ends with the release of NE into the BLA b. The other starts with E influence on Glu released by liver cells

20. What are the benefits of genetic engineering?

a. Permits more precise targeting of specific molecules that might play a role in making memories b. Can modify or detect gene of protein or tranfer new genes c. Possible to alter DNA of egg and alter specific genes d. DNA IS INJECTED INTO A PRONUCLEUS FROM A FERTILIZED EGG. THIS DNA CAN BE DESIGNED TO REPLACE/KNOCK OUT A PARTICULAR GENE OR IT CAN SUBSTITUTE FOR ANOTHER GENE

13. Protein synthesis induced by behavioral experience is thought to be critical for enduring memories. Based on what you know from the synaptic plasticity literature, what are the potential origins of the newly synthesized proteins?

a. Plasticity producs by CREB?

17. Describe the place-learning task.

a. Platform placed in bool below water, invisible to rodent b. Can escape by finding c. Has to learn location of platform and not just swim in one direction i. Placed in different locations d. The spatial learning version of the water-escape task was develop to study how animals aquire map-like representations of their environments.

12. Describe the inhibitory avoidance conditioning. What are two important attributes?

a. Procedure: rodent placed in bright side of apparatus. Rodents generally prefer to be in dimmer. When occurs, shock applied and subject removed. Repeats. Time in bright side increases because it remembers it was shocked. Rodent has to inhibit its tendency to cross over and avoid the place it was shocked b. Two attributes: i. Only one training trial is required ii. Rodents crossover latency is sensitive to the intensity of the shock

12. Describe the de novo protein synthesis hypothesis.

a. Protein synthesis is critical for the formation of LTM trace, but not for STM trace b. Synthesis of new proteins induced by training experience (not just protein levels) that is critical for consolidation i. Means protein synthesis inhibitor must be administered around time of behavioral experience if it is to prevent consolidation of LTM trace ii. Delaying administration for hours should have no effect on memory retention because trace will not have been consolidated c. Long-term memory depends on behavior initiating the synthesis of new protein

5. Defend this assertion. PKM is not a memory maintenance molecule.

a. Question that PKMz is essential for memory maintenance i. Reduntant molecules that can substitute

5. Describe the learning-performance distinction.

a. Recognizes the researcher has to be sure that the treatment exerted its effect by its influence on the memory component, an dnoot on some other component process that could also influence performance b. It recognizes the problem that the researcher has be sure that the treatment exerted its effect by its influence on the memory component and not on some other component process that could also influence performance.

2. How was the lentivirus approach used to study PKMζ? What two questions did it answer?

a. Rodent will acquire an aversion to novel taste that is followed by a drug that induces temp illness b. A single injection of ZIP in insular cortex will reduce a well consolidated taste aversion memory c. Lentivirus dominant negative PKMz construct competes with PKMz for expression. If it is injected into insular cortex 5 days following acquisition of memory, the memory is weakened d. Virus competes with functional PKMz for expression e. Injecting functional PKMz enhances established memories i. Injecting PKMz can prevent forgetting. ii. Can enhance already established memories

3. What are some of the many different component processes that make up measurable behavior? How do they affect the study of memory?

a. Sensory, attention, and perceptual processes that determine what the subject experiences at the time of testing b. Motivational processes that determine the subject's willingness to initiate a response c. Emotional processes that can interfere with a subjects ability to access stroed info d. Motor systems that provide the bases for the behavioral response to be expressed e. A memory system that stores the experience

6. Describe how short-term memory traces are different from long-term memory traces.

a. Short term memory trace i. Active state ii. Rapid decay iii. Vulderable to disruption b. Long term i. Inactive state ii. Slow decay iii. Less vulnerable to disruption

9. Differentiate between storage failure and retrieval failure. Can you provide an example of each?

a. Storage failure i. The agent that produces amnesia interferes with the processes for storing thte memory ii. Implication: events experienced prior will never be remembered. 1. A memory not storec can never be recovered. iii. PERMANENT AMNESIA b. Retrieval failure i. Memory stored but cant be accessed ii. Agent that produces amnesia disrupts neural pathways that enable retrieval iii. Amnesia is temporary c. Retrieval failure example i. Forgetting the location of a book or a coffee cup, only to remember it later,

3. Describe the results from experiments that used strychnine, a lethal poison, to study memory modulation.

a. Strychnine given after training enhanced memories produced by a variety of behavioral experiences b. There is a brief period of time shortly after the memory inducing behavioral experience when the strength of a memory trace can be modified c. At a low dose it is a stimulant and produces a state of arousal, and it was found to enhance memories produced by a variety of behavioral experiences.

14. Describe fear conditioning? What are three advantages of this method?

a. Study biological basis of memory b. Pavvlovian conditioning c. After rodent placed into conditioning chamber, and auditory stim (CS) presented d. 10-15sec after onset, shock (US) delivered e. Freezing is a CR used to assess rodents memory for the experience

1. Describe the basic research design used to provide evidence that a drug or genetic manipulation influences the consolidation of a long-term memory.

a. Subject trained on task (fear conditioning or inhibitory avoidance learning) b. 2 variables included i. Drug/genetic manipulation designed to influence target molecule ii. Retention interval c. Assumption: test performance at short retention intervals (less than 4 hours) is supported by short term memory tests, but that test performance at longer retention intervals requires a consolidated long term memory

Evidence for active decay theory

a. TBS applied to performant pathway to induce LTP in dentate gyrus of intact rats b. Within 4 days, decayed to baseline in vehicle. Decau was PREVENTED by daily systemic injections of an NMDA antagonist c. Rats learned a working memory task d. After 5 day retention interval, rats in the vehicle forgot task. Injections of NMDA antagonist prevented forgetting i. These results support the hypothesis that active molecular events initiated by small amounts of Ca actively depotentiate the synapse that support memory traces

2. What is the window to the memory trace?

a. The existence of a memory trace is inferred when training experience influences behavior, the test behavior is the memory trace i. Unless it can be shown that experience alters test behavior, there is no basis to say it establishes memory

2. What is the retention interval?

a. The time between the training experience that establishes the memory and the test used to retrieve the memory b. Ex)if drug impaired performance at 24 hour interval but not 1, result is consistent with the hypothesis that Mx is important for the consolidation of LTM trace not STM i. if same, would affect both STM and LTM

10. What is an example of time limited retrograde amnesia? Does it effect short term or long term memory? Is it a storage or retrieval failure?

a. Time limited retrograde amnesia: i. A failure to remember an experience that happened just prior to the occurrence of the disrupting event while remembering older experiences ii. Time limited retrograde amnesia is more likely to affect short-term memory b. Limited retrograde amnesia produced by a concussion likely affects only memories in the active state.

15. Discuss the pitfalls associated with using protein synthesis inhibitors like anisomycin to test the de novo protein synthesis hypothesis.

a. Toxic and may have side effects, including making animal ill b. Did drug impair LTM cuz protein synthesis or because it disrupted other processes needed to consolidate memory? c. Causes excessive release of NTs in region of injection and induces genomic signaling cascades in neuron that result in overproduction o fmRNA

21. What is viral vector system and how is it used?

a. Use of viruses to deliver new genetic material into specific cells b. Viruses have genetic material that provides basic instructions for self replications c. Cant replicate i. Must invade host d. Viruses can deliver desired genes into host cells e. In viral vector systems, the desired new genetic material is the VECTOR GENOME and the promoter sequence is THE ADDITIONAL GENETIC ELEMENTS that control the EXPRESSION OF THE GENE

22. What is the evidence that Insulin growth factor-II (IGF-2) is involved in memory consolidation?

a. Used IGF2 antisense to hippocampus b. Antisense infused within 8 hours of training impaired performance when retention interval was 24 hr, and infused up to 36 following impaired performance when retention interval was 48 hours c. Applied 104 hours following did not impair when interval 120 hr d. Impairment produced by antisense could be rescued by a coinfusion of IGF2 inhippocampus e. Continue to contribute to memory consolidation for over 24 hours f. Inhibitory avoidance training induces CREB-dependent transcription of IGF-2 mRNA and protein. Note that the mRNA level does not increase until about 20 hours after training. Protein level is also high 20 hours after training but not 72 hours later. (B) The consolidation of the inhibitory avoidance memory remains dependent on IGf-2 for at least 36 hours. IGF-2 antisense was infused into the hippocampus 8, 36, or 104 hours after training

19. What is the purpose of the visible-platform task?

a. Used as a control to evaluate effect of some brain manipulations on performance b. If a treatment has no effect on performance on the visible-platform task, then one would be more confident about concluding that the treatment influenced some aspect of memory. This is because the task makes no demand on spatial memory of the platform location.

8. How was electroconvulsive shock used in the past? How is it used in the study of memory?

a. Used by cerletti and bini to treat psychiatric disorderders. Clinical observations indicated patients treated with ECS often did not recall experiences during time leading up to treatment b. Duncan studied with amnesia and found rats that received ECS shortly after training displayed a memory impairment i. First to use ECS to induce amnesia in animals ii. When ECS administered within a minute after training, produced amnesia, but not when given an hour after iii. As memory aged, it became resistant to disruption, suggesting that memories need time to consolidate

9. Describe the essential experimental steps and results in the AMPA receptor trafficking experiments by Malinow's group (i.e., the Rumpel et al. experiments).

a. Used genetic engineering to create receptors and inject into amygdala i. Genetically engineered GluR1 AMPAs that had electrical conductance properies that were different from endogenout GluR1s b. Labeled receptors with fluorescent protein c. Used viral vector system to deliver these receptors into neurons located in the amygdala d. Expose mice to Fear conditioning stimulus to establish memory e. Take brains and tested slices to see if there was evidence of trafficking the engineered receptors i. Able to detect the presence of these receptors in synapses because when glu binds to them, electrical current can be detected that is slightly different from that produced by endogenous GluA1 receptors f. Stimulated auditory pathway in thalamus that projects to amygdala to activate synapses g. Results: conditioning experience had driven GluA1 receptors into the dendritic spines because they were able to detect an increase in signature response of synapses belong to neurons that fluoresced h. Second experiment:Dummy AMPA receptors compete endogenous receptors for delivery to synapses and impair fear conditioning and LTP i. Genetic engineering with creation of nonfunctional GluA1 that would compete ii. Nonfunctional can be driven into spine, but not respond to glutamate release iii. Results: reduced fear experience, measured by freezing response 1. Shows learning Depends on trafficking AMPA receptors with functional GluA1 subunits into the membrane

16. How might AMPA receptor trafficking be involved in memory modulation?

a. When NE released into hippocampus, PKA is activated and phosphorylates 2 sites (Ser831 and Ser845) on the GluA1 AMPA receptor subunitl. This facilitates the trafficking of GluA1s into the dendritic spine and increases memory strength b. Genetically deleting the Ser 831 and Ser 845 phosphorylation sites on the GluR1 receptor should: Impair L-LTP and the effect of norepinephrine on AMPA receptor trafficking c. Originally GluA1 subunit trafficked (calcium permeable)

20. What is working memory? What is reference memory?

a. Working memory- maintains and manipulates info to solve a particular problem or achieve a particular goal b. Reference memory-memory for the arms of the radial maze that consistently contain the reward i. In the radial arm maze methodology, if a rat revisits an arm that was never baited, it is making a reference memory error. ii. In the radial arm maze methodology, if a rat revisits an arm, it is making a working memory error.

16. Discuss the assertion: The two mTOR complexes make different contributions to consolidation.

a. mTORC1 regulates signaling cascades that increase local protein synthesis i. inhibited by rapamycin b. mTORC2 regulates processes that contribute to the regulation of actin i. insensitive to rapamycin

8. Describe the temporal relationship between phosphorylated CREP (pCREB) and the C/EBP

a. pCREB phosphorylates C/EBPb i. takes hours to notice increase ii. suggests construction of the memory trace may continue for longer period than one would anticipate from LTP experiments b. C/EBPb is a transcription factor and can target transcription of other genes that may be needed to establish enduring memories c. Increased levels of pCREB present in hippocampus shortly after training, and remain high for at least 20 hr d. Increasing levels of C/EBPb mRNA are not observed until 9 hours after training e. C/EBPb antisense infused into the hippocampus 5 and 24 hours after training impaired retention of the inhibitory avoidance memory i. Rats were tested 48 hr after training f. Results indicate that C/EBPb protein dependent processes operate at least 24hr following training

4. What is the function of epinephrine in the body? Where is it secreted? How is it different from norepinephrine?

i. Mobilize for behavioral action ii. Secreted from adrenal gland (adrenal medulla) iii. Norepinephrine also secreted by medulla but in smaller quantities that can act as a NT in the brain iv. Epinephrine can influence strength of a memory trace v. Epinephrine in the blood stream binds to adrenergic receptors on the vagus nerve, which synapses on the NTS, which in turn synapses on the locus coeruleus (LC) and those neurons project to the forebrain, hippocampus, and amygdala. b. NE function i. Enhances memories

CREB overexpression

i. Used inter-trial interval (time separating light) ii. When ITI was 10s, LTM was poor compared to 8s iii. Injecting virus that expresses CREB into LA prior to conditioning trial can eliminate impaired LTM for 10s iv. Able to acquire LTM of light shock experience

b. mTORC2 complex can be altered by genetically deleting rictor component

i. complex important for LTM and enduring LTP ii. contributes to long term changes in synaptic strength by regulating actin dynamics iii. rictor KO mice display normal STM for fear conditioning, impaired LTM iv. jasplakinolide (JPK) promotes actin polymerization and rescues LTM impairment v. TBS 1. Induces early phase short lasting LTP in rictor KO mice, but not late phase LTP 2. The regulation of actin dynamics and signaling is disrupted in Rictor KO mice 3. Ratio of F to G actin is a measure of the level of actin polymerization 4. It is reduced in rictor KO mice 5. pCofilin required for polymerization, but reduced in KO mice 6. impaired LTM and LTP are due to in part by impaired actin regulation in the rictor KO mice

17. What is the evidence that proteins translated in response to the mTORC1 signaling are important for the consolidation of long-term memory but not for producing a short-term memory?

i. inhibited by rapamycin ii. when infused to amygdala prior to inhibitory avoidance training, does not interfere with performance when retention interval is 3 hrs, but impairs when 24 iii. suggest signaling cascades regulated by mTORC1 are important for memory consolidation iv. local protein synthesis v. regulates mRNA translation through activating downstream targets like p70s6k and 4E-BP