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LO: Compare the two main theories of memory consolidation

ANSWER- multiple trace model of consolidation (right diagram with red and green traces) The standard model does not fully explain the retrograde amnesia observed in HM that went back decades because his neocortex was intact. The standard model would suggest that any OLD memory from decades ago should be stored and consolidated ONLY in the cortex and safe from the hippocampal damage in patient HMs brain. If the standard model is true those old memories for patient HM should still be intact, but unfortunately for him they were not. From your text... Many observations about memory formation are consistent with the standard model, but questions have been raised about whether it provides the most accurate account of consolidation. A key point is the duration of retrograde amnesia. For example, early accounts of H.M.'s amnesia reported that his retrograde amnesia extended back a few years. An interpretation of this observation is that synaptic consolidation is completed quickly but systems consolidation takes years to complete and the retrograde memories H.M. lost were ones not "fully baked" (i.e., engrams still dependent on the hippocampus). Later studies examined H.M.'s retrograde amnesia in more detail and found that it extended back decades. Perhaps systems consolidation is a very slow process that takes decades. However, some scientists have asked whether this makes sense in a species whose individuals, not so long ago, lived only for a few decades. As if that question isn't confusing enough, it should be noted that later studies of H.M. suggested that he had retrograde amnesia for episodic memories that extended back virtually his entire life. This implies that the hippocampus, perhaps in concert with other medial temporal structures, may be involved with memories for a lifetime

LO: Describe at least two pieces of experimental evidence that support the idea that the MTL supports declarative memory LO: Identify the structures of the medial temporal lobe (MTL) and describe how information flows through the MTL

Animal model of human amnesia Studies of macaque medial temporal lobe using experimental ablation Delayed match-to-sample and delayed non-match to sample (DNMS) tests Recognition memory tasks Amygdala and hippocampus not significantly involved in recognition memory Much still unknown about specific brain areas Collectively, medial temporal structures critical for consolidation of memory Delayed non-match to sample •Monkey faces a table with small wells on the surface, first sees the well with one object covering the well •Monkey is trained to remove the object and find a food reward beneath •After the monkey gets the reward a screen is used to prevent the monkey from seeing the table for some period of time (delay interval) •After the delay interval, the monkey gets to see the table again but now there are two objects on it (one is the same as before and one is new) •In DNMS, the monkey has to displace the NEW object to get the reward • •Similar to HM, amnesia was anterograde, declarative rather than procedural, working memory was intact, and consolidation was severely impaired!

ASSOCIATIVE LEARNING:

Behavior altered by formation of associations between events (In contrast to changed response to a single stimulus) Classical conditioning (Pavlov) Pairing of unconditional stimulus with conditional stimulus

LO: Discuss the relationship between CREB, protein synthesis and memory by providing research examples

CREB & protein synthesis Protein synthesis inhibitors block LTM consolidation. Animals learn normally but fail to remember the test days later Deficit in LTM if inhibitors are injected shortly after training Memories become resistant to the inhibition of protein synthesis as the interval between the training and the injection of inhibitor is increased New protein synthesis is important during period of memory consolidation (STM → LTM)

LO: Compare and contrast how CaMKII and PKMzeta remain persistently active and evidence for their roles in memory consolidation

CaMKII Activated by Calcium Autophosphorylating kinase Keeps AMPA receptors phosphorylated- MAINTENANCE OF SYNAPTIC POTENTIATION Molecular switch hypothesis- authophosphorylating kinase can store info at the synapse Ten subunits Other CaMKII comments: Remember from last week, activation of CaMKII is required for LTP! CaMKII stays on for a long time after calcium levels fall. Because each subunit can autophosphorylate the next. The initial activation of CaMKII by calcium is strong→ it will stay on! The hingelike subunit of CaMKII is normally "off" when the catalytic region is covered by the regulatory region. The hinge opens upon activation of the molecule by Ca2+-bound calmodulin, freeing the catalytic region to add phosphate groups to other proteins. A large elevation of Ca2+ can cause phosphorylation (P) of one subunit by another (autophosphorylation), which enables the catalytic region to stay "on" permanently.

Amnesia: serious loss of memory and/or ability to learn

Causes: concussion, chronic alcoholism, encephalitis, brain tumor, stroke Limited amnesia (common)—caused by trauma Dissociated amnesia: no other cognitive deficits (rare) Retrograde amnesia: memory loss for things prior to brain trauma Anterograde amnesia: inability to form new memories after brain trauma

LO: Compare and contrast input specificity and cooperativity

Cooperativity - enough synapses active simultaneously to cause spatial summation and LTP at multiple synapses Subsequent research has shown that high-frequency stimulation is not an absolute requirement for LTP. Rather, what is required is that synapses be active at the same time that the postsynaptic CA1 neuron is strongly depolarized. In order to achieve the necessary depolarization with a tetanus, (1) synapses must be stimulated at frequencies high enough to cause temporal summation of the EPSPs, and (2) enough synapses must be active simultaneously to cause significant spatial summation of EPSPs. This second requirement is called cooperativity, because coactive synapses must cooperate to produce enough depolarization to cause LTP. Consider for a moment how the cooperativity property of hippocampal LTP could be used to form associations. Imagine a hippocampal neuron receiving synaptic inputs from three sources: I, II, and III. Initially, no single input is strong enough to evoke an action potential in the postsynaptic neuron. Now imagine that inputs I and II repeatedly fire at the same time. Because of spatial summation, inputs I and II are now capable of firing the postsynaptic neuron and of causing LTP. Only the active synapses will be potentiated, and these, of course, are those belonging to inputs I and II. Now, because of potentiation of their synapses, either input I or input II can fire the postsynaptic neuron (but not input III). Thus, LTP has caused an association of inputs I and II. In this way, the sight of a duck could be associated with the quack of a duck (they often occur at the same time), but never with the bark of a dog.

LO: Describe how a cell assembly could support memory

Cortical cells are involved in memory too! When I make my grandmothers carmel cake, the smell of it triggers an entire memory of her and her kitchen for me. Its not that the smell of carmel cake activates all the neurons representing the memory But rather activation of just part of the engram (olfactory sensory neurons in the cortex) triggers activation of the entire memory trace Another example of this is from a famous popular neuroscience book "The man who mistook his wife for a hat". In this book, a man has had damage to the olfactory nerve (his cribriform plate was crushed) and he has anosmia (good review of some of our olfaction discussions). The book provides an interesting detailed description of what his anosmia was like, but also discusses how he was able to "smell" coffee even though from a physiological perspective there was no activity in the damaged olfactory nerve. It must be that the visual stimulus activated a Hebb network (i.e. memory engram) of the coffee memory sufficient to trigger the perception of smell from the cortical memory. We can also think of pain in this way. Remember phantom limb pain. Pain in a limb that is missing. It must be activation of the memory engram for that pain from other sensation that triggers the memory and perception of that pain even when the nociceptors are gone. Memory Stimulation Activation of some of the cortical cells via sensory input (maybe just the smell of the rose) within a cell assembly, then these cells are reciprocally interconnected with others involved with the memory to stimulate perception of that event External events are represented in cortical cells. Cells reciprocally interconnected à reverberation Simultaneously active neurons—cell assembly Consolidation by "growth process" "Fire together, wire together" Lesion experiments supporting role for cortex in memory Lashley's rat experiments Cortical lesions produce memory deficits. Speculated all cortical areas contribute equally (equipotential) - this is NOT the case, Equipotential capacity later disproved But memory engrams can be widely distributed in the brain

LO: Compare the two main theories of memory consolidation LO: Propose at least one practical implication of reconsolidation

Declarative memory formation involves system of interconnected brain structures: Take in sensory information Make associations between related information Consolidate learned information Store engrams for later recall Components include hippocampus, cortical areas around hippocampus, diencephalon, neocortex, and more.

Propose at least one practical implication of reconsolidation

Drug Tweaks Epigenome to Erase Fear Memories https://www.nationalgeographic.com/science/phenomena/2014/01/22/drug-tweaks-epigenome-to-erase-fear-memories/#close A HURRICANE, A car accident, a roadside bomb, a rape — extreme stress is more common than you might think, with an estimated 50 to 60 percent of Americans experiencing it at some point in their lives. About 8 percent of that group will be diagnosed with post-traumatic stress disorder, or PTSD. They will have flashbacks and nightmares. They will feel amped up, with nerves on a permanent state of high alert. They won't be able to forget. One of the only effective treatments for PTSD is 'exposure therapy,' in which people are repeatedly exposed to their fear — such as a painful memory — in a safe context. This treatment works partly because of how our brain encodes memories. Whenever we actively recall a memory, it transforms into a pliable molecular state and becomes vulnerable to modification. About half of people who get exposure therapy for PTSD get better. But that still leaves a lot of people who don't. A mouse study published last week in Cellpublished last week in Cell throws the spotlight on a drug that acts in concert with exposure therapy to help extinguish fear memories. The drug works by changing the epigenome, the chemical markers that attach to DNA and can turn genes on and off. "It's remarkable," says Li-Huei Tsai, a neuroscientist at the Massachusetts Institute of Technology who led the work. "If we inject a single dose of this drug it actually is sufficient to reactivate neuroplasticity." The drug works by changing the way DNA is expressed in the brain. In order to fit into the nucleus of each cell, DNA wraps tightly around spherical proteins called histones. (You can see how in this animation.) Histones are littered with chemical groups, such as methyl and acetyl, that influence how nearby genes get turned on and off. For many years, Tsai has been studying enzymes called histone deacetylases, or HDACs, which switch off genes by removing acetyl groups from histones. In 2012, she showed that one such enzyme, dubbed HDAC2, is overactive in a mouse model of Alzheimer's disease and shuts down genes related to learning. In that study she also showed that blocking HDAC2 led to dramatic gains in the animals' memory. "HDAC2 is a master regulator of the expression of neuroplasticity genes," Tsai says. "And HDAC inhibitors seem to be very beneficial for memory formation." In the new study, Tsai's team investigated whether this enzyme is also involved in the way that fear memories cement themselves into brain circuits. Mice don't get PTSD, but they can acquire fear memories. Using so-called Pavlovian fear conditioning, researchers train the animals to fear a particular cue, such as a sound or smell, by pairing it with a mild shock to the foot. After a few trials, the animal freezes at the cue alone. There's also a mouse version of exposure therapy. After a mouse learns to fear, say, a certain tone, researchers can extinguish that fear by repeatedly playing the tone without a shock. Gradually the animal learns to associate the tone with the safer context. But in mice (and, importantly, in some people with severe PTSD), this extinction therapy only works for recently acquired fear memories. If a fear memory is old, then no amount of retraining will erase the animal's fear. "One of the major challenges in developing treatments for PTSD is that traumatic memories can persist for a lifetime," notes Matt Lattal, a neuroscientist at Oregon Health and Science University who was not involved in the new study. "It is therefore critical that laboratory models of PTSD include this long interval between traumatic experience and testing." Tsai and her colleagues trained mice to fear a tone and then gave them extinction therapy either a day later or 30 days later. When extinction training happened a day later, the HDAC2 enzyme was inactivated in brain cells, the study found. With HDAC2 quiet, acetyl groups stayed latched on to histones and various memory genes stayed on. Presumably, this window of plasticity allowed the mice to un-learn the fear memory. In contrast, when extinction training happened 30 days later, the HDAC2 enzyme was active. It removed those acetyl groups, effectively shutting off neuroplasticity genes. But here's the exciting part. The animals were able to un-learn the fear memory 30 days after it was formed when the researchers paired extinction therapy with a drug that inhibits HDAC2, dubbed "CI-994." It only took one dose, and the researchers saw no side effects, Tsai says. "We did a lot of control experiments to show that this mechanism doesn't wipe out other memories. It really is very specific to the training condition." HDAC inhibitors are becoming a hot class of drugs. In 2012, Yossef Itzhak and his colleagues at the University of Miami reported that giving a different HDAC inhibitor to mice before they acquire the fear memory accelerates the extinction of the memory weeks later. "Hypothetically speaking, HDAC inhibitors may be useful prophylactics against the persistence of fear memory," says Itzhak, who was not involved in the new study. Researchers are investigating HDAC inhibitors for all sorts of other conditions, too, including heart disease, HIV, and cancer. Because HDAC enzymes are expressed all over the body, though, some experts are worried about their translation into the clinic. "HDAC inhibitors have a wide spectrum of biological effects, and only when they will be targeted for the treatment of a specific malady [will] their therapeutic value be of great importance," Itzhak says. "The goal is to identify specific HDAC inhibitors which target specific brain circuits and genes."

LO: Evaluate how an enriched environment affects learning

Enriched Environment Exposure Accelerates Rodent Driving Skills Highlights •Rats can learn the complex task of navigating a car to a desired goal area. •Enriched environments enhance competency in a rodent driving task. •Driving rats maintained an interest in the car through extinction. •Tasks incorporating complex skill mastery are important for translational research.

LO: Consider how structural plasticity contributes to learning and memory LO: Evaluate how an enriched environment affects learning

Long-term memory associated with formation of new synapses Rat in complex environment: shows increase in number of neuron synapses by about 25% Altering visual or tactile environment stimulates formation of new dendritic spines. Limits to structural plasticity in adult brain But the end of a critical period does not necessarily signify an end to structural changes

LO: Describe the evidence that LTP and LTD are involved with memory

LTP and LTD have attracted a lot of interest because theoretical work shows that these mechanisms of synaptic plasticity can contribute to the formation of declarative memories. Recent research indicates that the types of NMDA receptor-dependent synaptic plasticity that have been characterized in the hippocampus also occur throughout the neocortex, including area IT where memories of familiar faces are created (Figure 25.16). It appears that plasticity at many synapses in the cerebral cortex may be governed by similar rules and might use similar mechanisms. (But remember, there are many exceptions to these "rules," and they do not apply to all synapses, even within a single structure.)

LO: Summarize evidence supporting the role of the hippocampus in navigation

London taxi drivers - interesting correlation between the size of the hippocampus and time spent as a taxi driver Posterior hippocampus volume increases while anterior volume decreases Patient TT → london taxi driver for 40 years that suffered damage to hippocampus after enchephalitis. Sometimes he could drive efficiently through a virtual London city and sometimes not. Did a good job when he could stick to main rodes but got lost when smaller road navigation was required. He lost the fine-grained knowledge of the city he once had. (kind of the like radial arm lesion results in unbaited and baited arms) Humans have place cells too!

LO: Describe at least two pieces of experimental evidence that support the idea that the MTL supports declarative memory

HM - most famous patient in neuroscience. I remember when he died in 2008 and we learned his name for the first time. Seizures from around age 10, severe Age 27 had 8cm length of medial temporal lobe bilaterally excised, including cortex, amygdala, and anterior 2/3 of hippocampus Severe anterograde amnesia resulted (inability to form new declarative memories!) He did retain some memories of childhood. Little to No memories for events just before surgery Retrograde amnesia may have gone back decades He did learn new floor plan of his home after the surgery and he was able to learn new tasks (new procedural memories) Medial temporal lobe is critical for memory consolidation

LO: Examine how lesions of the hippocampus affect spatial memory

Hippocampal Lesions Radial arm maze Normal rats are efficient go down each arm of the maze for food only once! Lesioned rats never learn this efficiency! (go down the same arms more than once - no food after the first trip). Rats do seem to learn that they go down the arms in search of food (procedural memory) but can't remember which arms they already visited Radial arm maze with only some arms baited As long as the no-food arms are always the same each time, lesioned rats can learn to avoid the no-food arms. But they will still go down food arms multiple times (inefficiently) Working memory is disrupted but procedural is intact Lesioned rats: unlike normal rats, they never learn to do this efficiently. Rats with hippocampal lesions go down the same arms more than once, only to find no food after the first trip, and they leave other arms containing food unexplored for an abnormally long time. It appears that the rats can learn the task in the sense that they go down the arms in search of food (the procedural memory). But they cannot seem to remember which arms they've already visited. But how come rats learn to avoid the no-food arms, yet continue to explore those arms inefficiently? the key to making sense of these findings is that the information about the no-food arms is always the same each time the rat goes in the maze (i.e., no-food arms are memorized as part of the "procedure"), whereas the information about which arms the rat has already entered requires working memory and varies from one trial to the next.(PhD 847)

LO: Discuss the memory functions of the hippocampal system

Hippocampal lesions & recordings demonstrate its role in odor discrimination → forming associations between sensory stimuli (like odor) Neurons would respond only when a specific odor was at a specific port (relate odor with its spatial location). And lesions result in deficits in this discrimination task Odor discrimination task description : rats cage has two ports with two different odors For each pair of odors the animal is trained to approach one odor and not the other Some neurons in the hippocampus become selective for certain pairs of odors. Neurons were even selective for which odor was at which port. Hippocampal neurons are relating specific odors to their spatial location!

LO: Define LTP and how the EPSP changes after LTP

Hippocampus-where LTP has been most researched Long term potentiation- long lasting increase in the strength of a synapse based on recent patterns of neuronal activity Why most researched - easy to dissect out (cut like a loaf of bread) simplified circuit. Can be kept alive with ASCF and bubbling oxygen and then sliced into brain slices for electrophysiology. Known role in learning and memory from lesion studies like Patient HM & rodent studies discussed last session

LO: Consider how structural plasticity contributes to learning and memory

How does the synapse make use of the timely occurrence of gene expression and the arrival of a new protein? One possibility is that newly synthesized proteins (such as PKMζ) switch local synaptic protein synthesis on in order to maintain a synaptic change. However, to account for the fact that blocking protein synthesis fails to disrupt memories that have already been consolidated, we would have to further posit that these newly synthesized proteins have a lifespan that is long enough to survive the temporary inhibition of protein synthesis. Another possibility is that the lasting imprint of new protein synthesis is the construction (or demolition) of synapses. Work on the invertebrate Aplysia has shown that some types of long-term (but not short-term) memory can cause a doubling of the number of synapses made by some neurons!

LO: Discuss the memory functions of the hippocampal system

If we think back to the approaches discussed in our text and our prior class session for understanding the function of the MTL (medial temporal lobe) 1)Temporal lobe amnesia in humans (HM) à Study human patients with hippocampal lesions 2)Electrical stimulation of temporal lobes à stimulate the hippocampus in patients undergoing neurosurgery and ask for them to report perceptions, etc. 3)Recordings from temporal lobes à record from neurons in the hippocampus while animals or humans perform behavioral tasks 4)Temporal lobe amnesia in animals (delayed non-match to sample) à lesion the hippocampus in animals

LO: Describe at least two pieces of experimental evidence that support the idea that the MTL supports declarative memory

In addition to the HM lesion studies Electrical stimulation and neural recordings from the MTL indicate this region is important for declarative memory! Medial Temporal Lobes Important for consolidation and storage of declarative memories Demonstrated by: Electrical stimulation in the temporal lobe Neural recordings from the temporal lobe

In addition to the HM lesion studies Electrical stimulation and neural recordings from the MTL indicate this region is important for declarative memory! Temporal lobe stimulation Effects different from stimulation of other areas of neocortex Penfield's experiments Stimulation à sensations like hallucinations or recalling past experiences Temporal lobe: apparent role in memory storage Caveat: complex sensations reported by minority of patients, all with a need for brain surgery (epilepsy) Recording the MTL of Humans ØNeurons preferentially respond to categories of objects including faces, household object and outdoor scene ØEven more selectivity in small percentage of these neurons (Jennifer Aniston or Michael Jordan, Halle Berry- face, drawings, text of her name even fig 24.15), neurons selective for Eiffel tower, etc. ØInvariant neurons—respond to variety of images are structurally or conceptually related ØMany questions remain.

LO: Propose at least one practical implication of reconsolidation

In another of Loftus's studies (Loftus & Palmer, 1974), students watched a film of a traffic accident and then estimated how fast the cars were traveling. Researchers asked some students, "About how fast were the cars going when they hit each other?" For other students, the researchers replaced the word hit with smashed, collided, bumped, or contacted. The estimated speeds varied with the word used in the question, with contacted resulting in the lowest speeds and smashed producing the highest.

LO: Discuss the relationship between CREB, protein synthesis and memory by providing research examples

In their first series of experiments, Tully and Yin bred Drosophila that would make extra copies of the fly's version of CREB-2 (called dCREBb) when the animal was warmed up (a miracle of fly genetic engineering that is not possible in mammals). This manipulation repressed all gene expression that is regulated by the CREs, and also blocked memory consolidation in a simple memory task. Thus, CREB-regulated gene expression is critical for memory consolidation in fruit flies. More interesting, however, is what they found when they generated flies that could make extra copies of fly CREB-1 (called dCREBa). Now, tasks that would take normal flies many trials to learn could be remembered after a single training trial. These mutant flies had a "photographic" memory! And these results are not peculiar to flies; CREBhas been implicated in regulating the consolidation of sensitization in Aplysia, as well as long-term potentiation and spatial memory in mice.

LO: Describe the properties & mechanisms of LTD in CA1

LTD in CA1 Define LTD- long lasting decrease in the strength of a synapse based on recent patterns of neuronal activity Discuss how to induce LTD - low frequency stimulation How can both LTD & LTP induction require NMDA receptors & calcium entry? All about concentration- low levels of calcium result in LTD Synaptic transmission occurring at the same time as weak or modest depolarization of the postsynaptic neuron causes LTD At some synapses the timing is key (i.e. when EPSP follows an AP in postsynaptic neuron) NMDA receptor dependent - when weak depolarization of postsynaptic neuron only a little calcium comes through Different calcium levels activate different calcium enzymes → phosphatases (remove phosphorylation from AMPA receptors and cause internalization of AMPA receptors) Also mGLUR dependent form (we don't discuss)

LO: Describe the properties & mechanisms of LTD in CA1

LO: Define LTP and how the EPSP changes after LTP

LTP = long term potentiation EPSP = excitatory post synaptic potential LTP means there has been an increase in the magnitude of the recorded EPSP in the postsynaptic neuron after some event (i.e. tetanus stimulation). Now the same baseline stimulation results in a larger depolarization (i.e. larger EPSP) of the post synaptic neuron. Go back and look at the y-axis on the previous slide showing LTP. The y-axis is EPSP magnitude and after a tetanus we see LTP an increase in the EPSP magnitude

LO: Describe the evidence that LTP and LTD are involved with memory

LTP and LTD are clearly appealing models, but what evidence links them to memory? (1) So far, all we've described is a possible neural basis for a memory of having one's brain electrically stimulated! One approach has been to insert stimulating and recording electrodes in the hippocampus and use these to monitor the state of synaptic transmission during learning. Because of the distributed nature of memory, success with this approach required the use of a particularly robust type of learning called inhibitory avoidance. In this experiment, a rat learns to associate a place (the dark side of a box) with an aversive experience (a foot shock) (Figure 25.17a). Animals of all types (from flies to humans) will learn to avoid the place they received the shock after only one trial (depending, of course, on the strength of the shock). This type of learning is not subtle, and neither are the patterns of hippocampal activation it produces. The widespread activation of the hippocampus after inhibitory avoidance training gave researchers the opportunity to detect changes in synaptic transmission at Schaffer collateral-CA1 synapses, and voilà!—LTP was observed (Figure 25.17b). In other experiments, exposing animals to a novel environment without a foot shock caused LTD instead. These experiments tell us that learning does indeed induce LTP and LTD at hippocampal synapses. (2) Another approach has been to see whether the molecules involved in LTP and LTD are also involved in learning and memory. For example, both forms of synaptic plasticity require activation the of NMDA receptors. To assess the possible role of hippocampal NMDA receptors in learning, researchers injected an NMDA receptor blocker into the hippocampus of rats undergoing inhibitory avoidance training. This treatment prevented formation of a memory of the aversive experience. These experiments built on pioneering studies performed by Richard Morris in the late 1980s at the University of Edinburgh, in which NMDA receptor blockers were infused into the hippocampus of rats while they were being trained in a water maze (see Figure 24.20). Unlike normal animals, these rats failed to learn the rules of the game or the location of the escape platform. This finding provided the first evidence that NMDA-receptor-dependent processes play a role in memory. (3) A revolutionary new approach to the molecular basis of learning and memory was introduced by Susumu Tonegawa at the Massachusetts Institute of Technology. Tonegawa, who switched to neuroscience after winning the 1987 Nobel Prize for his research in immunology, recognized that molecules and behavior could be connected by manipulating the genes of experimental animals. This approach had already been tried with success in simple organisms like fruit flies (Box 25.5), but not in mammals. In their first experiment in mice, Tonegawa, Alcino Silva, and their colleagues "knocked out" (deleted) the gene for one subunit (α) of CaMKII, and found parallel deficits in hippocampal LTP and memory. Since then, many genes have been manipulated in mice, with the aim of assessing the role of LTP and LTD mechanisms in learning. LTP, LTD, and learning clearly have many common requirements. Despite the power of this genetic approach, it has some serious limitations. Loss of a function, like LTP or learning, might be a secondary consequence of developmental abnormalities caused by growing up without a particular protein. Moreover, since the protein is missing in all cells that normally express it, pinpointing where and how a molecule contributes to learning can be difficult. For these reasons, researchers have attempted to devise ways to restrict their genetic manipulations to specific times and specific locations. In one interesting example of this approach, Tonegawa and his colleagues found a way to restrict the genetic deletion of NMDA receptors to the CA1 region in mice, starting at about 3 weeks of age. These animals showed a striking deficit in LTP, LTD, and water maze performance, thus revealing an essential role for CA1 NMDA receptors in this type of learning. (4) If too little hippocampal NMDA receptor activation is bad for learning and memory, what would happen if we boosted the number of NMDA receptors? Amazingly, animals engineered to produce more than the normal number of NMDA receptors show enhanced learning ability in some tasks. Taken together, the pharmacological and genetic studies show that hippocampal NMDA receptors play a key role not only in synaptic modification, such as LTP and LTD, but also in learning and memory.

LO: Describe the properties of LTP in CA1 LO: Define LTP LO: Compare and contrast input specificity and cooperativity

LTP in CA1 (Schaffer collateral CA3→ CA1) Bliss and Lomo in 1973 discovered that a Tetanus = burst of HFS (100/s) produced LTP LTP is a LONG lasting increase in the strength of a synapse based on recent patterns of neuronal activity Look at the graph: on the x axis we have time. On the y axis we have the EPSP magnitude. BEFORE the HFS we measure the baseline EPSP size AFTER HFS the size of the EPSPs increases! Remember EPSP = excitatory post synaptic potential most excitatory and inhibitory synapses can support LTP INPUT SPECIFICITY ONLY active inputs show the synaptic plasticity Without tetanus, there is no LTP for input 2 → input specificity. ONLY the synapse with high activity (tetanus of input 1) will produce LTP LTP can last for many months in freely moving animals (at least a year): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693170/ Figure legend from text: (a)The response of a CA1 neuron is monitored as two inputs are alternately stimulated. LTP is induced in input 1 by giving this input a tetanus. (b) The graph shows a record of the experiment. The tetanus to input 1 (arrow) yields a potentiated response to stimulation of this input. (c) LTP is input-specific, so there is no change in the response to input 2 after a tetanus to input 1. ● From your text: In 1973, an important discovery was made in the hippocampus by Timothy Bliss and Terje Lømo, working together in Norway. They found that brief, high-frequency electrical stimulation of the perforant path synapses on the neurons of the dentate gyrus produced LTP. It was subsequently shown that most excitatory (and many inhibitory) synapses support LTP, and that the mechanisms can vary from one synapse type to another. However, the most sophisticated understanding of LTP has come from studying the Schaffer collateral synapses on the CA1 pyramidal neurons in brain slice preparations. This will be our focus. In 1973, an important discovery was made in the hippocampus by Timothy Bliss and Terje Lømo, working together in Norway. They found that brief, high-frequency electrical stimulation of the perforant path synapses on the neurons of the dentate gyrus produced LTP. It was subsequently shown that most excitatory (and many inhibitory) synapses support LTP, and that the mechanisms can vary from one synapse type to another. However, the most sophisticated understanding of LTP has come from studying the Schaffer collateral synapses on the CA1 pyramidal neurons in brain slice preparations. This will be our focus.

LO: Distinguish the difference between induction mechanisms and expression mechanisms LO: Compare and contrast the role of AMPA and NMDA receptors in LTP

LTP induction requires AMPA and NMDA receptors AMPA (alpha amino 3 hydroxy 5 methyl 4 isoxazoleproprionic acid) Sodium (not calcium) flows through the channel when open Glutamate alone is sufficient to open the channel No Mg++ Responds to the drug AMPA - agonist (where the name comes from!) NMDA (N-methyl-D-aspartate) Glutamate alone is insufficient to open the channel Mg++ under resting conditions blocks the channel pore Depolarization and Glutamate required to open the channel Na+ and calcium flow through the channel (calcium acts as a second messengerà CaMKII à CREB à transcription and synaptic changes-BDNF dendritic branching) Responds to NMDA BOTH Ligand (glutamate) gated ion channel (i.e. Ionotropic receptors) AMPA receptor inhibition by synaptically released zinc Bopanna I. Kalappaa, Charles T. Andersona, Jacob M. Goldbergb, Stephen J. Lippardb, and Thanos Tzounopoulosa,c,1 aDepartment of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261; bDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; and cDepartment of and Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261 Edited by Robert C. Malenka, Stanford University School of Medicine, Stanford, CA, and approved November 9, 2015 (received for review June 23, 2015) The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synap- tic transmission is implicated in nearly all aspects of brain develop- ment, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we pro- vide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR syn- aptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses. Zinc Effects on NMDA Receptor Gating Kinetics Stacy A. Amico-Ruvio, Swetha E. Murthy, Thomas P. Smith, and Gabriela K. Popescu* Department of Biochemistry, University at Buffalo, Buffalo, New York ABSTRACT Zinc accumulates in the synaptic vesicles of certain glutamatergic forebrain neurons and modulates neuronal excitability and synaptic plasticity by multiple poorly understood mechanisms. Zinc directly inhibits NMDA-sensitive gluta- mate-gated channels by two separate mechanisms: high-affinity binding to N-terminal domains of GluN2A subunits reduces channel open probability, and low-affinity voltage-dependent binding to pore-lining residues blocks the channel. Insight into the high-affinity allosteric effect has been hampered by the receptor's complex gating; multiple, sometimes coupled, modulatory mechanisms; and practical difficulties in avoiding transient block by residual Mg2þ. To sidestep these challenges, we examined how nanomolar zinc concentrations changed the gating kinetics of individual block-resistant receptors. We found that block- insensitive channels had lower intrinsic open probabilities but retained high sensitivity to zinc inhibition. Binding of zinc to these receptors resulted in longer closures and shorter openings within bursts of activity but had no effect on interburst intervals. Based on kinetic modeling of these data, we conclude that zinc-bound receptors have higher energy barriers to opening and less stable open states. We tested this model for its ability to predict zinc-dependent changes in macroscopic responses and to infer the impact of nanomolar zinc concentrations on synaptic currents mediated by 2A-type NMDA receptors.

LO: Describe the evidence that LTP and LTD are involved with memory

LTP, LTD and memory Inhibitory Avoidance Training •rodents are naturally inclined to head to the dark side. Normal preference for the dark side •In this type of learning (inhibitory avoidance), rats associate the dark side with an aversive shock •Animals of all types will learn to avoid a place they received a shock after only one trial •LTP was detected in the hippocampus during this learning •In other experiments, exposing the animals to a novel environment without a foot shock caused LTD instead NMDA receptor antagonist (APV) infusion in brain will block LTP and impair learning (ex. Morris water maze) NMDA Receptor blocker in hippocampus prevents avoidance learning shown in the figure Mice that overexpress NMDA receptors have enhanced LTP and better memory Figure shown: LTP in CA1 is induced by learning - electrodes were implanted in the rat's hippocampus to measure EPSPs before and after avoidance training Rats prefer dark side to avoid light so when you open the barrier they run in. But a foot shock is delivered! Was a memory created → measure (latency) time it takes for the rat to re-enter the dark side at various time points after the experience. Recordings of LTP in CA1 when this type of memory is formed. Novel environments without foot shock cause LTD CaMKII KO's show hippocampal LTP & memory deficits NMDAR KO in CA1 starting around 3 weeks of age → deficits in LTP, LTD & water maze learning Slices removed from humans during surgery show LTP and LTD in IT (memory of faces)

LO: Define Learning and Memory

Learning and memory: lifelong brain adaptation to environment Several similarities between experience-dependent brain development and learning Similar mechanisms at different times and in different cortical areas Memories range from stated facts to ingrained motor patterns. Anatomy: several memory systems Evident from effects of brain lesions Definitions: Learning is the acquisition of new knowledge or skills. Memory is the retention of learned information.

LO: Compare and contrast declarative and nondeclarative memory

Learning: acquisition of new information Memory: retention of learned information Types of Memory: Declarative memory (explicit) Facts and events- We can remember events and tell our friends about them! What did you do over spring break this year? Nondeclarative memory (implicit) Procedural memory—motor skills, habits

LO: Evaluate how striatal and hippocampal lesions impact procedural memory.

Lesions in striatum disrupt procedural memory (habit learning) —but not declarative memory Standard radial arm maze performance (declarative memory) depends on hippocampus. Modified radial arm maze performance (performance memory) depends on striatum. Damaged hippocampal system: degraded performance on standard maze task Damaged striatum: impaired performance of the modified task Performance on the two versions of the radial arm maze task were affected in markedly different ways by two types of brain lesions. If the hippocampal system was damaged (in this case, with a lesion to the fornix that sends hippocampal output), performance was degraded on the standard maze task but was relatively unaffected on the light version. Conversely, a lesion in the striatum impaired performance of the light task but had little effect on the standard task. This "double dissociation" of the lesion site and the behavioral deficit suggests that the striatum is part of a procedural memory system but is not crucial for the formation of declarative memories.

LO: Discuss the memory functions of the hippocampal system

Memory formation, retention, and retrieval involve a system of interconnected brain areas. Considerable evidence points to the importance of the medial temporal lobe for declarative memory, and within this region of the brain the hippocampus has received the greatest attention. It's not simple to pin down just what the hippocampus does, however, as it is involved in various memory functions at multiple time scales

LO: Discuss how synaptic homeostasis impacts LTP/LTD induction at active versus silent synapses

Metaplasticity: (think of metaplasticity as the plasticity of plasticity ) Synaptic modification threshold NMDA receptor activation between that required for LTD and for LTP. Threshold moves with the history of activity. Too much LTD, threshold slides down making LTD less likely and LTP easier to produce When activity rises, the modification threshold slides up. If activity levels fall, the modification threshold slides down.

LO: Consider how structural plasticity contributes to learning and memory

Muscle fibers in background Individual axons in yellow Single synapses in red At birth in rats this tree is very elaborate, but actually the number of red connections with muscle decrease with the age of the rat. As certain connections are strengthened and others are lost. activity -dependent synaptic plasticity and memory formation in the adult brain have much in common with those operating during development for wiring the brain Hebb Memory results from synaptic modifications.

LO: Describe the stages of memory acquisition and memory consolidation

LO: Describe the mechanisms of LTP in CA1 LO: Distinguish the difference between induction mechanisms and expression mechanisms. (induction and expression are shown in this image) LO: Compare and contrast the role of AMPA and NMDA receptors in LTP

NMDA Receptors are coincidence detectors •They detect simultaneous presynaptic and postsynaptic activity (remember neurons that fire together wire together) •Calcium entry through the NMDA receptor is CRITICAL for modifying the synaptic strength •Many experiments have demonstrated that a consequence of STRONG NMDAR activation is the strengthening of synaptic transmission (i.e. LTP) From your text: Perhaps NMDA receptors serve as Hebbian detectors of simultaneous presynaptic and postsynaptic activity, and Ca2+entry through the NMDA receptor channel triggers the biochemical mechanisms that modify synaptic effectiveness. Tests of this hypothesis have been performed by electrically stimulating axons to monitor the strength of synaptic transmission before and after an episode of strong NMDA receptor activation (Figure 23.29a, b). Results consistently indicate that a consequence of strong NMDA receptor activation is a strengthening of synaptic transmission called long-term potentiation (LTP).

TODAY's LO: Compare and contrast declarative and nondeclarative memory LO: Distinguish habituation, sensitization, classical conditioning, & instrumental conditioning

Operant conditioning: Animals will learn to press a lever for food, for water, for drugs, for electrical stimulation that releases DA, etc. Drugs that block dopamine receptors reduced self-stimulation, suggesting that the animals were working to stimulate the release of dopamine in the brain. This idea was further supported when researchers discovered that animals will press a lever to receive an injection of amphetamine, a drug that releases dopamine in the brain. Although there is more to electrical self-stimulation than dopamine, there is little question that dopamine release in the brain will reinforce the behavior that causes it. These experiments suggested a mechanism by which natural rewards (food, water, sex) reinforce particular behaviors. Indeed, a hungry rat will press a lever to receive a morsel of food, and this response is also greatly reduced by dopamine receptor blockers. (PhD 566)

LO: Explain why phosphorylation of proteins as a long-term memory consolidation mechanism is problematic

Phosphorylation insufficient as long-term memory consolidation mechanism Phosphorylation of a protein is not permanent. Memories would be erased. Protein molecules themselves are not permanent. Other mechanisms needed for long-term consolidation Protein kinases Protein synthesis

LO: Use a diagram to illustrate the properties of place cells LO: Summarize evidence supporting the role of the hippocampus in navigation

Place Cells in Humans several research studies show recordings from place cells identified during virtual navigation of environment. Nature 2003 Ekstrom et al 317 neurons in human medial temporal and frontal lobes. Cells that respond to specific spatial locations and cells that respond to views of landmarks! Still not a neuron firing as a human move around their real environment. Think about neurosurgery when most often human neurons are recorded from. The patient isn't up walking around! PET imaging has shown that human hippocampus is activated in situations involving virtual or imagined navigation Hippocampus is activated when navigating from one point to the other (without a guide) Caudate activation is thought to reflect movement planning

LO: Propose at least one practical implication of reconsolidation

Profound implications for eye witness testimony and treatment of stress associated with unpleasant memories (PTSD) Eyewitness testimony. Please watch this video about eyewitness testimony, please be advised the first part discusses a sexual assualt: https://youtu.be/DZsckuKiH94 You have probably heard of people convicted of crimes based on eyewitness testimony and the convicted person is later released from prison based on DNA evidence proving their innocence. Evidently the memory of the eyewitness had been wrong. Might this happen in some cases because witnesses are coached and the coached information interacts and reconsolidates with the events of the recalled crime? Ongoing research is examining the conditions under which reconsolidation can occur; the results have important implications for the judicial system and our ability to trust our own memories PTSD If we are able to alter memories after they have been consolidated, perhaps a process can be devised to treat people with memories that haunt them. In post-traumatic stress disorder (PTSD), an earlier traumatic event has serious deleterious effects on later behavior, mood, and social interactions, even in nonthreatening situations. An example is a war veteran who experiences stress and fear in daily life long after the war is over. What if there was a way to erase or at least weaken such unpleasant memories? Studies exploring this question suggest that it might be possible. An MIT experiment shows promise for treating PTSD (excerpt from your text)... We don't know if mice experience PTSD, but a recent study by Tsai and her colleagues at MIT attempted to reduce an unpleasant memory in mice by targeting neural plasticity rather than affecting whole-body physiology as with propranolol. As in experiments we have already examined, mice are made to fear a loud sound by pairing the sound with an electrical foot shock. When mice later hear the sound they freeze in fear even if the foot shock is not given. The usual way to decrease the strength of the fear reaction is to repeatedly expose the mice to the sound without giving an electrical shock (similar to the treatment humans with PTSD are given in which they recall a traumatic memory in a safe environment). This extinction therapy in the mice is found to reduce or eliminate fear associated with the chamber if the therapy is started one day after the traumatic experience but not 30 days later. With an eye toward the delayed treatment of PTSD in humans, Tsai et al aimed to reduce the memory in mice a month after the electrical shock, a time at which extinction therapy alone is ineffective. This was accomplished by combining the fear-inducing sound with administration of a drug that inhibits the HDAC2 (histone deacetylase 2) enzyme. This enzyme, which switches neuroplasticity genes off in the nucleus of neurons (discussed in Chapter 25), was found to be inactive the day after the electrical shock but active a month later. By inhibiting HDAC2, the plasticity genes were activated at the later time. With the genes active and the traumatic memories revived by the loud sound, it was possible to reconsolidate the memory in a less fearful form. After just one dose, the mice no longer froze when the sound was heard. We don't know if this or a related approach will work to treat human PTSD, but there is hope that memory reconsolidation might be of use in alleviating this disorder.

LO: Compare and contrast how CaMKII and PKMzeta remain persistently active and evidence for their roles in memory consolidation

Protein Kinase M Zeta Phosphorylates proteins that regulate AMPA receptor numbers Phosphorylates proteins that regulate mRNA translation Stays on long after Calcium Translation of the kinase mRNA is activated by Calcium ZIP specifically inhibits the kinase ZIP zaps memories (Zip can erase LTP and memories established many days before the injection Role in maintenance of LTP and certain forms of memory Sacktor and colleagues "ZIP zaps memories" Maintains changes in synaptic strength by continuing to phosphorylate substrates Specific mechanisms still unclear.

LO: Describe the concept of synaptic tagging

Protein Synthesis and Consolidation Protein synthesis required for formation of long-term memory Protein synthesis inhibitors Deficits in learning and memory New protein synthesis required during the period of memory consolidation Synaptic Tagging and Capture Experiments of Julietta Frey and Richard Morris Weak stimulation endows synapses with a tag. Enables them to capture newly synthesized proteins that consolidate LTP An event that would otherwise be forgotten might be seared into long-term memory If it occurs within 2 hours of a momentous event that triggers a wave of new protein synthesis Molecular mechanisms still not fully understood Protein Synthesis Strong stimulation → long lasting LTP that requires protein synthesis When you stimulate input 1, weakly (enough to get LTP) PRIOR to strong stimulation of input 2 (protein synthesis occurs) what happens? The wave of new proteins can be captured by the input 1 synapses! Cause long lasting LTP. Reviewing an item we discussed earlier can help make it stick! Kinases hypothesized to be involved

LO: Discuss the relationship between CREB, protein synthesis and memory by providing research examples

Protein synthesis inhibitors block LTM consolidation. Animals learn normally but fail to remember the test days later Deficit in LTM if inhibitors are injected shortly after training Memories become resistant to the inhibition of protein synthesis as the interval between the training and the injection of inhibitor is increased New protein synthesis is important during period of of memory consolidation (STM → LTM) CREB: cyclic AMP response element binding protein Functions to regulate expression of neighboring genes Tully and Yin- CREB regulates gene expression required for memory consolidation. CREB1 - promotes transcription (needs to be phosphorylated) CREB 2 - blocks transcription OVERexpress CREB 2 → blocks transcription (repressed gene expression) → block memory consolidation and performanc in simple memory task OVERexpress CREB 1→ "photographic" memory, learn a task in a single training rather than many (drosophila evidence) Also evidence in Aplysia and mice (spatial memory)

LO: Propose at least one practical implication of reconsolidation

Rat experiments Reactivating a memory makes it sensitive to change as when first formed (before consolidation) Reconsolidation: the reactivation effect Human reconsolidation experiments Recalling a memory makes it susceptible to change Hippocampal activity Profound implications for eye witness testimony and treatment of stress associated with unpleasant memories

Propose a real-world implication of reconsolidation

Reactivating a memory makes it sensitive to change as when first formed (before consolidation) Reconsolidation: the reactivation effect Human reconsolidation experiments Recalling a memory makes it susceptible to change Profound implications for eye witness testimony and treatment of stress associated with unpleasant memories •Relatively simple measures can help reform eyewitness ID procedures. •Lineup administrators should NOT know who the suspect is. •Research shows that administrators often provide unintentional cues to the eyewitness about who to pick •Fillers should match the witness's description •Lineup administrator SHOULD get a statement articulating the witness's confidence •Our state has implemented reform!!

LO: Propose at least one practical implication of reconsolidation

Reconsolidation-The process of retrieving, modifying, and storing a memory that was previously consolidated. Think of Sadness's ability to color Riley's core memories in INSIDE OUT EVERY time we retrieve a memory, it becomes susceptible to change think back to the radio lab podcast about implanted memories that you listened to. before todays class! We can implant memories about getting lost in a shopping mall. Told participants that they had talked to their parents. Do you remember this event and start with a true story. In the middle of all the true stories they would slip in a lie. About 25% of subjects would believe a memory that never happened. Long-term Memory (LTM) has a VAST capacity but is subject to distortion. The memory trace- the record laid down by an experience (network of neurons that encode the memory)- is interfered with by other events occurring before or after The process of retrieving information from LTM can cause memories to become unstable and susceptible to disruption and alteration

LO: Compare and contrast declarative and nondeclarative memory LO: Distinguish habituation, sensitization, classical conditioning, & instrumental conditioning

Sensitization (B) is a form of learning where your response intensifies to a stimulus, even when previously that stimulus evoked little or no reaction You live in a busy city where horns honk all the time and don't get much reaction out of you. A few hours ago you were in a car accident and now any horn honk startles you tremendously habituation (A) is learning to ignore a stimulus that lacks meaning (in a big city you quickly become habituated to sound of cars going by, noise of the city, etc.)

Compare the two main theories of memory consolidation

Since the time of H.M., a view of memory consolidation and storage has developed that has come to be called the standard model of memory consolidation. In this model, information comes through neocortex areas associated with sensory systems and is then sent to the medial temporal lobe for processing (especially the hippocampal system). As we will discuss in more detail in Chapter 25, changes in synapses create a memory trace via a process sometimes called synaptic consolidation (Figure 24.25a). After synaptic consolidation, or perhaps overlapping with it in time, systems consolidation occurs in which engrams are moved gradually over time into distributed areas of the neocortex (Figure 24.25b). It is in a variety of neocortical areas that permanent engrams are stored. Before systems consolidation, memory retrieval requires the hippocampus, but after systems consolidation is complete, the hippocampus is no longer needed. Alternatives to the standard model have been proposed, most notably the multiple trace model of consolidation proposed by Lynn Nadel of the University of Arizona and Morris Moscovitch of the University of Toronto. The multiple trace model was proposed as a way to avoid the necessity of the decades-long systems consolidation process the standard model needs to account for extended retrograde amnesia. If hippocampal damage disrupts episodic memories going back decades or a lifetime, perhaps the hippocampus is always involved in memory storage. In other words, systems consolidation does not ever relinquish engrams entirely to neocortex. According to this theory, engrams involve neocortex, but even old memories also involve the hippocampus (Figure 24.25c). The term "multiple trace" refers to the way the model allows for retrograde amnesia resulting from hippocampal damage to sometimes be graded in time. The hypothesis is that each time an episodic memory is retrieved, it occurs in a context different from the initial experience and the recalled information combines with new sensory input to form a new memory trace involving both the hippocampus and neocortex. This creation of multiple memory traces presumably gives the memory a more solid foundation and makes it easier to recall. Because retrieval requires the hippocampus, complete loss of the hippocampus should cause retrograde amnesia for all episodic memories no matter how old. If there is partial damage, then the memories that are intact would be the ones with multiple traces. To the extent that older memories would have been recalled more times than recent memories, they would be more likely to survive hippocampal damage, and this would give rise to a temporal gradient in retrograde amnesia. Suffice it to say that at present experts disagree about assessments of gradients in retrograde amnesia and the validity of various models of consolidation.

LO: Use a diagram to illustrate the properties of place cells

Spatial Memory & Place Cells- Recording from the hippocampus 2014 Nobel Prize Place cells fire when an animal is in a specific place. They are dynamic! When you remove the partition the place field moves. We did not discuss grid cells today, but grid cells respond when an animal is at multiple locations that form a hexagonal grid From your text.... (figure 24.21 is shown above on the left) What properties of hippocampal neurons aid them in their spatial navigation and memory? In a fascinating series of experiments begun in the early 1970s, John O'Keefe and his colleagues at University College London showed that many neurons in the hippocampus selectively respond when a rat is in a particular location in its environment. Suppose we have a microelectrode implanted in the hippocampus of a rat while it scurries about inside a large box. At first the cell is quiet, but when the rat moves into the northwest corner of the box, the cell starts firing. When it moves out of the corner, the firing stops; when it returns, the cell starts firing again. The cell responds only when the rat is in that one portion of the box (Figure 24.21a). This location, which evokes the greatest response, is called the neuron's place field. We try recording from another hippocampal cell and it too has a place field, but this one fires only when the rat goes to the center of the box. For obvious reasons, these neurons are called place cells. Performance in the radial arm maze, discussed above, may utilize these place cells that code for location. Of particular importance in this regard is the finding that place fields are dynamic. For instance, if the box the animal is in is stretched along one axis, place fields will stretch in the same direction. In another manipulation, we first let a rat explore a small box and determine the place fields of several cells. Then we cut a hole in a side of the box so the animal can explore a larger area. Initially, there are no place fields outside the smaller box, but after the rat has explored its new expanded environment, some cells will develop place fields outside the smaller box (Figure 24.21b). These cells seem to learn in the sense that they alter their receptive fields to suit behavioral needs in the new larger environment. It's easy to imagine how these sorts of cells could be involved in remembering arms already visited in the radial arm maze, just as you might return from a long hike by following markers you left when you first walked through the woods. If hippocampal place cells are involved in running the maze, it makes sense that performance is degraded by destroying the hippocampus.

LO: Describe the stages of memory acquisition and memory consolidation

Stages of Memory - encoding → storage → retrieval → reconsolidation Encoding includes: acquisition and consolidation Acquisition of short term memory = physical modification caused by incoming sensory info Modification of transmission between neurons STM survives distraction but will be forgotten unless consolidated to LTM No neuron spared - virtually every neuron in the NS can form memory of recent patterns of activity Consolidation - requires new gene expression & protein synthesis While it might appear that I am doing nothing, at the cellular level I am really quite busy

LO: Describe the mechanisms of LTP in CA1 LO: Distinguish the difference between induction mechanisms and expression mechanisms LO: Identify molecular changes at the pre-synaptic and post-synaptic level that can produce LTP

Structural plasticity The molecular changes we just discussed on the previous two slides are accompanied by physical changes to the synaptic connection. The dendrite gets larger and we can visualize this in living animals and in hippocampal slices and neurons in a dish Figure legend: A segment of dendrite was filled with a fluorescent dye and imaged in living tissue using a special microscope. After LTP, the spines grew and sometimes sprouted to accommodate new synapses. Each frame is a snapshot of the dendrite at a different time, indicated in the upper-right corner (in minutes). At the time marked 0 min, the yellow dot indicates that this spine was repetitively activated with glutamate to induce LTP. After LTP, the spine grew to accommodate more AMPA receptors. (Photos courtesy of Dr. Miquel Bosch, Massachusetts Institute of Technology.) From text: Evidence also indicates that synaptic structure changes following LTP. In particular, postsynaptic dendritic spines appear to bud and form new synaptic contacts with axons. Thus, following LTP, a single axon can make multiple synapses on the same postsynaptic neuron, which is not the normal pattern in CA1. This sprouting of synapses not only increases the responsive postsynaptic surface but also increases the probability that an action potential in the axon will trigger presynaptic glutamate release.

LO: Discuss the memory functions of the hippocampal system

The Hippocampus: "What happened, where" •HM studies à declarative memory consolidation •Hippocampal rat lesion studies, rat neuron recordings (place cells) & human imaging studies à spatial memory •Recording neurons in humans à selectivity for people (Halle Berry) and objects (Statue of Liberty) •Hippocampal lesions & recordings demonstrate its role in odor discrimination à forming associations between sensory stimuli (like odor) • The hippocampus links different experiences together A summary (to check your learning) from our text... Let's summarize the diverse studies of the hippocampus we've discussed. First, research since the time of H.M. indicates that the hippocampus is critical for memory consolidation of facts and events. Strong evidence suggests that in rodents, and in people, the hippocampus is especially important for spatial memory. In recordings from human hippocampal neurons there is sometimes surprising selectivity for people or objects we are familiar with. Finally, hippocampal cells appear to form associations between sensory stimuli even when the information is not about space. A thread that runs through these various studies is that the hippocampus links different experiences together. It receives a huge spectrum of sensory inputs and may construct new memories by integrating the varied sensory experiences associated with an event (e.g., the theme music of a television show is integrated with memories of people and place). The hippocampus may also be essential for building or enhancing memories by connecting new sensory input with existing knowledge. It has been suggested that the input from the grid cells in the entorhinal cortex provides "where" information to the hippocampus, while other input contains information about "what." The neural associations constructed and then consolidated in the hippocampus might effectively establish memories for "what happened where."

Describe the stages of memory acquisition and memory consolidation

Training your brain: synaptic plasticity We can alter circuits in adulthood. He did learn how to ride the bike but it took SO much longer than his son. Our brain is much more plastic as children than in adulthood

LO: Describe the differences between retrograde and anterograde amnesia

Transient global amnesia (re-listen to the radio lab podcast for a refresher which was pre class work) Sudden onset of anterograde amnesia Lasts a shorter period, from temporary ischemia (e.g., severe blow to head) Symptoms: disoriented, ask same questions repeatedly; attacks subside in couple of hours; permanent memory gap Working Memory vs Short term Memory Remember working memory is information that is "held in mind" like a phone number (working on the order of seconds). Working memory might be converted into long term but most of it is discarded when no longer needed Short term memories are held on the order of hours. Working memory is distinguished from short term memory by tht every limited capacity ,need for repition, short duration. HM's had memory consolidation deficits HM's working memory & procedural memory were also largely in tact suggesting that must use distinct brain structures! Medial temporal lobe is critical for memory consolidation but not for the retrieval of memories

LO: Describe the anatomy of the hippocampus

Tri-synaptic Circuitry (1) Major input to hippocampus from entorhinal cortex via bundle of axons call perforant path Perforant path axons synapse on DG neurons. (2) DG neurons give rise to mossy fiber axons that synapse on CA3 neurons (3) CA3 neurons give rise to axons that branch, one branch called the Schaffer collaterals and form synapses on CA1 neurons

LO: Evaluate how an enriched environment affects learning

The blue lines represent animals from an enriched environment. They enter the car faster and achieve driving milestones more quickly and are the only group to meet final criterion of 4 full drives. Having that enriched environment makes these rats better learners for a complex task. What does this say about our experiences as children and how they may set us up for future learning

LO: Compare and contrast declarative and nondeclarative memory

Types of Memory: Declarative memory (explicit) Facts and events Nondeclarative memory (implicit) Procedural memory—motor skills, habits Types of procedural A type of nondeclarative memory Involves learning a motor response In reaction to sensory input Occurs in two categories of learning Nonassociative learning. (single stimulus) Associative learning Types of Declarative memory Working memory. (we won't discuss in too much detail but will mention in memory 2) Temporary storage, lasting seconds Short-term memories—vulnerable to disruption Facts and events stored in short-term memory Subset are converted to long-term memories. Long-term memories Recalled months or years later Memory consolidation: process of converting short- to long-term memories From your text Declarative memory- During the course of our lives, we learn many facts (e.g., the capital of Thailand is Bangkok, Darth Vader is Luke Skywalker's father). We also store memories of life's events (e.g., "Yesterday's neuroscience exam was fun!" or "I went swimming with my pet dog named Axon when I was five years old.") Memory of facts and events is called declarative memory (Figure 24.1). A declarative memory distinction we will examine later on is between episodic memory for autobiographical life experiences and semantic memory for facts. Declarative memory is what people usually mean in everyday uses of the word "memory," but we actually remember many other things too. Explicit memory-declarative memory is often called explicit memory, because it results from more conscious effort Types of non-declarative memory (implicit memory) procedural memory, or memory for skills, habits, and behaviors. We learn to play the piano, throw a Frisbee, or tie our shoes, and somewhere that is stored in our brain. Associative learning- Classical conditioning! Involves reflexive behavior Conditioned stimulus and unconditioned stimulus. Conditioned and unconditioned response. Pavlov's dogs and salivation Operant learning (i.e. instrumental learning)- animal behavior is a result of its consequences. Behaviors that result in positive consequences increase. Like an animal that learns pressing a lever will deliver food. The animal will continue pressing the lever

Fear Conditioning

US = Shock UR = Freezing & increase in blood pressure CS = tone CR = Freezing & increase in blood pressure

Always try and identify the US, UR, CS, & CR when you are studying pavlovian (classical) conditioning.

US = food UR = salivation CS = bell CR = salivation

LO: Consider how structural plasticity contributes to learning and memory LO: Evaluate how an enriched environment affects learning

Very recently advances in microscopy have made it possible for researcher to image the same neuron in living mice over the course of days/weeks. Altering sensory stimulation you can observe the formation of new dendritic spines From your text... Do similar structural changes occur in the mammalian nervous system after learning? This is a difficult problem to solve experimentally because of the complexity of the mammalian brain and the distributed nature of memory. One approach has been to compare brain structure in animals that have had ample opportunity to learn with that of animals that have had little chance to learn. For example, putting a laboratory rat in a "complex" environment filled with toys and playmates (other rats) has been shown to increase the number of synapses per neuron in the occipital cortex by about 25%. Very recently, advances in microscopy and methods for cell labeling (see Box 2.1) have made it possible for researchers to image the same neuron in living mice over the course of many days. Altering the visual or tactile environment stimulates the formation of new dendritic spines, important sites of excitatory synaptic transmission, in the visual and somatosensory cortex, respectively (Figure 25.22). As exposure to this new environment is increased, these new synapses grow larger and other synapses on the same dendrites are eliminated, as would be expected if the mechanisms of LTP and LTD are at work to encode a memory. The new spines may shrink if the animal is returned to the original environment but do not disappear, consistent with the interpretation that these persistent spines contribute to a long-term memory of the altered environment

Review LO: Describe the mechanisms of LTP in CA1 Review LO: Distinguish the difference between induction mechanisms and expression mechanisms. (induction and expression are shown in this image) Review LO: Compare and contrast the role of AMPA and NMDA receptors in LTP

We have seen that memory can result from experience-dependent alterations in synaptic transmission. In most examples of synaptic plasticity, transmission is initially modified as a result of changing the number of phosphate groups that are attached to proteins in the synaptic membrane. In the case of LTD and LTP, this occurs at the postsynaptic AMPA receptor and at proteins regulating AMPA receptor number at the synapse. Adding phosphate groups to a protein can change synaptic effectiveness and form a memory, but only as long as the phosphate groups remain attached to that protein. Phosphorylation as a long-term memory consolidation mechanism is problematic for two reasons: 1.Phosphorylation of a protein is not permanent. Over time, the phosphate groups are removed, thereby erasing the memory. 2.Protein molecules themselves are not permanent. Most proteins in the brain have a lifespan of less than 2 weeks and are undergoing a continual process of replacement. Memories tied to changes in individual protein molecules would not be expected to survive this rate of molecular turnover. Thus, we need to consider mechanisms that might convert what initially is a change in synaptic protein phosphorylation to a form that can last a lifetime.

LO: Describe at least two pieces of experimental evidence that support the idea that the MTL supports declarative memory

We just discussed subtypes of memory, but how do we know this? Evidence Implicating Medial Temporal Lobes in consolidation and storage of declarative memory: 1)Electrical stimulation of temporal lobes 2)Recordings from temporal lobes 3)Temporal lobe amnesia in humans (HM) 4)Temporal lobe amnesia in animals (delayed non-match to sample)

LO: Discuss how synaptic homeostasis impacts LTP/LTD induction at active versus silent synapses

What is a silent synapse? Wikipedia definition = "a silent synapse is an excitatory glutamatergic synapse whose post synaptic membrane contains NMDA receptors but NO AMPA receptors." Curiously, when a glutamatergic synapse first forms, only NMDA receptors appear in the postsynaptic membrane. As a consequence, released glutamate at a single synapse evokes little response when the postsynaptic membrane is at the resting potential. Such "silent" synapses announce their presence only when enough of them are active at the same time to cause sufficient depolarization to relieve the Mg2+ block of the NMDA receptor channels. In other words, "silent" synapses "speak" only when there is highly correlated activity, the necessary condition for synaptic enhancement during development.

LO: Examine how lesions of the hippocampus affect spatial memory

With training the time it takes for the animal to escape to the platform decreases. They remember where the platform is! From your text... Several lines of evidence suggest that the hippocampus is particularly important for spatial memory. The Morris water maze, a commonly used test of spatial memory in rats, was devised by Richard Morris of the University of Edinburgh. In this test, a rat is placed in a pool filled with cloudy water (Figure 24.20). Submerged just below the surface in one location is a small platform that allows the rat to escape the water. A rat placed in the water the first time will swim around until it bumps into the hidden platform, and then it will climb onto it. Normal rats quickly learn the spatial location of the platform and on subsequent trials waste no time swimming straight to it. Moreover, once they have figured out what to search for, rats put in a maze with the platform at a different location learn the task much faster. But rats with bilateral hippocampal damage never seem to figure out the game or remember the location of the platform.

Is LTP easier to induce in highly active (mature) or silent synapses? Click on your choice then discuss your rationale with your group

silent synapses -> easier to induce LTO

that can produce LTP Post-synaptic Depolarization plus pre-synaptic glutamate release → NMDA receptor opening → calcium entry → CaMKII → CREB → gene expression & long lasting changes The lists below apply to this slide and the next slide Post synaptic (purple on next slide) More AMPA receptors expressed More AMPA receptors moved to post synapse and on edges of synpatic cleft AMPA receptors phosphorylated → stay open longer → more depolarization from the same amount of glutamate release More PSD95- bigger "egg carton" to hold more "eggs" (i.e. AMPA receptors) More AMPA receptors with GluR1 subunit BDNF involved in growth, dendrite makes branches, spines increase, dendritic branching More NMDA receptors made •Immature synapse contain NMDA receptors but few AMPA receptors but as they mature more AMPA receptors •Thus, the strong activation of NMDA receptors that occurs when pre- and postsynaptic neurons fire together appears to account, at least in part, for why they wire together during visual system development •Dendritic spines grow and even split following LTP Presynaptic (grey on next slide) Nitric Oxide Decreased Threshold for AP firing Increased release of neurotransmitter (increased number of loaded vesicles primed for release) Axon expansion Release of transmitter from additional sites From your text What accounts for LTP of the synapse? One consequence of the strong NMDA receptor activation, and the resulting flood of Ca2+ into the postsynaptic dendrite, is the insertion of new AMPA receptors into the synaptic membrane (Figure 23.29c). Such "AMPAfication" of the synapse makes transmission stronger. In addition to this change in the complement of glutamate receptors, recent evidence suggests that the synapses can actually split in half following LTP induction, forming two different sites of synaptic contact. Cortical neurons grown in a tissue culture form synapses with one another and become electrically active. The immature synapses contain clusters of NMDA receptors but few AMPA receptors. Consistent with the idea that LTP is a mechanism for synaptic maturation, electrically active synapses gain AMPA receptors over the course of development in cell culture. This change fails to occur, however, if NMDA receptors are blocked with an antagonist. Thus, the strong activation of NMDA receptors that occurs when pre- and postsynaptic neurons fire together appears to account, at least in part, for why they wire together during visual system development. (We will discuss LTP and its molecular basis further in Chapter 25.)

final info yay

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