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Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 1 of 7 Abbreviations: LTP= long-term potentiation, CS= Conditioned Stimulus, US= Unconditioned Stimulus, UCR= unconditioned response, CR= conditioned response, AP= action potential Synaptic Plasticity I. Synaptic Plasticity [S1] a. We will follow along with Dr. Wyss’s lecture about learning and memory so we will go back into the hippocampus. He used Pavlov’s dog to show procedural learning in the cerebellum (e.g. the conditioned eye blink reflex). b. Humans do most of their learning in an associative manner. We can take Pavlov’s dog and extend it to declarative memory, things that are transiently stored in parts of the brain, like the hippocampus, and then stored in the cortex. c. We know this because we all have pneumonics that we use to remember things. d. The reason associative memory is useful is because it is like storing information by imagining it like a puzzle, the information is different parts of the puzzle but we only need to see little parts of the puzzle to recall the whole memory or the whole puzzle to identify what the puzzle is. e. We can store things by association things get associated with one another and we don’t need to remember the whole thing just a part of it to get everything to come back out. f. We will use Pavlov’s dog again, and if you keep that in mind, what he will try to show us at the cellular level of current understanding with how associative memories may be stored through the hippocampus and then on into the cortex. g. Associative means we are associating two things together to form a memory. We look for mechanisms that may be two pathways, come together, and change something. At the molecular level, the change is at the receptor the NMDA receptor i. It’s an important receptor for remembering and forgetting. ii. The NMDA is a molecular plasticity switch in the brain. iii. Highest density of NMDA receptors is in the hippocampus h. Wednesday’s lecture about addiction, think about addiction as a form of associative learning. Those with addiction problems have associated cues that trigger cravings. II. Learning objectives [S2] a. Understand the properties of long-term potentiation (LTP) that define it as a model of experience-dependent synaptic plasticity i. Might have heard of LTP. This is an activity dependent (experience dependent) change in synaptic strength. The synapse may keep stimulating synapses to get a response of x, and if we do something to the synapse that may involve learning or associating pathways, we change that response and it gets bigger and stays bigger for a long time. b. Discuss the characteristics that make NMDA receptors coincident detectors cable of initiating associative information storage (Pavlov’s dog) i. NMDA is a glutamate receptor; remember glutamate is primary excitatory transmitter in the brain. c. Describe the relationship between NMDA receptors, LTP and behavioral memory i. How this is involved in real learning III. Learning & memory in taxi drivers [S3] a. Study done in humans b. Took cab drivers from London and gave them a memory recall task. i. They had to imagine picking up passengers at some location and dropping them off somewhere in London. They had to recall it based on spatial information; they did not have a map to trace the route, so they had to use spatial recall. When they did this, they found that the left temporal lobe lit up, where you find the hippocampus, which is involved in recall. c. Short and LTP- the hippocampus is important for changing short term information into long term information. d. The case about HM - had good short term memory (as long as he didn’t get distracted) but couldn’t put it into long term memory e. Hippocampus provides a special role in limbic system that is associated with the Papez’s circuit for encoding spatial information, so there are place maps in that area. f. During recall you expect to see parts of the brain associated with specific tasks light up. g. Memory that is visual, you will see visual cortex responding. IV. Papez Circuit/Loop [S4] a. Know this Papez circuit within the limbic system and this is the only bit of anatomy we need to know and it illustrates a lot of parts in the limbic system b. Hippocampus is in the temporal lobe, we get information leaving by the fimbria and fornix around to the mamillary bodies. We have the mammillothalamic tract to the anterior thalamus. Up to anterior cingular cortex throughout cortex and back out to hippocampus- know this memory circuit Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 2 of 7 c. Other information that feeds into circuit: amygdala, temporal lobe, other parts of the brain, striatum, olfactory bulb V. Place cells / maps [S5] a. Don’t’ remember details but just know at a single cell level there are cells in the hippocampus that are place cells b. If you put an animal in a novel environment, the cells start to encode for direction or position within the environment c. If the animal is facing a certain way, some cells will prefer that certain orientation, as in visually direction sensitive cells in the retina. So depending on what direction the animal is facing, the cells fire AP or become silent. d. If an animal wanders around this environment, some cells respond strongly when it is in a particular location and then turn off, and another set will turn on at that location, so it seems that it encodes space. e. [SQ]: visual feedback and dependence [A]: It requires visual information to form place cell. Once it is encoded in the same environment, and it doesn’t have to rely on visual cues totally. The exact details of the place maps are being worked out. We do know that they extend from the hippocampus to the cingular cortex, so the entire area is involved. f. We have to get from the cells (synapses) in hippocampus to understand how learning happens VI. Hebbian learning….in theory [S6] a. Hebb was a psychologist. b. Idea is that if you have repeated conjoint activity between pre and postsynaptic cells, then you can have a change in synapses that connects the cells. c. The pre and postsynaptic cell is active, the synaptic strength changes and that is Hebb’s postulate, and several years later that was demonstrated physiologically. VII. Synapses are plastic [S7] a. How do we make synapses remember things? We encode things by pattern of AP. For a location on the body, it will ultimately result in an AP being initiated and going up to the brain. b. The frequency of AP may tell you something about intensity. c. The frequency or pattern of activity may be important to tell if you should modify the synaptic strength, maybe you should make it stronger or weaker. d. At NMJ: stimulate one AP at the motor neuron and recording synaptic response to NMJ. e. Stimulate one AP and in the next one the response stays stable, you get a similar response. High frequency train of AP, the responses get bigger and stay bigger for a while then fade back down. f. One idea about changing the synaptic path, you alter the pattern of information coming back g. Synapses “remember” previous activity i. Only remembers things for a second or so then goes back to normal, which is good for muscles cell to contract and then go back to resting position and to do that reliably. ii. Any memory control occurs centrally VIII. Can synaptic plasticity explain learning? [S8] a. Does it result in a different outcome if done in CNS? Remember Dr. Wyss told us about learning and memory, so maybe the rain deals with this differently. b. Pavlov’s dog slide we have seen before- we don’t have to go into too much other than remember what is the CS and these US c. CS is something that produces a neutral weak outcome but can be altered when paired with the US because the US produces a strong response d. We will map those inputs onto the hippocampus IX. Learning Objective #1 [S9] a. Understand the properties of long-term potentiation (LTP) that define it as a model of experience-dependent synaptic plasticity X. Figure of hippocampus [S10] a. Hippocampus is down in the temporal lobe. b. Circuit where information goes through, cycles around, and passes back out. You might have recurrent looping of information, with information coming in and looping back out several times and we decide if it goes out to permanent storage. c. Orientation information comes in from entorhinal cortex, the adjacent cortex, and it starts to feed into the proper neo cortex. i. The Neo cortex is a 6 layered structure, and the hippocampus cortex has 3 layers and does connect with neo cortex via the entorhinal cortex. d. Input comes in, synapses on one set of cells in the dentate gyrus, which is sometimes not referred to as hippocampus proper. Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 3 of 7 e. Those cells synapse with another set of cells, CA3 pyramidal cells, and those make connections with CA1 pyramidal cells. f. So there are 3 synapses all serially organized and all of them can undergo LTP g. Information comes out, these cells go to the subiculum and we can see how it loops into the entorhinal cortex and out. The axons bifurcate and the information can pass out via the fornix and fimbria can go from subiculum cells to the CA3 pyramidal cells. h. The CA3 takes information to the other hippocampus but this is our main output to the fornix and back around to the mammary bodies. i. Overall: know 3 synapses all have glutatmate and all can undergo plasticity. j. As Dr. Wyss said, if we lesion CA1 part, ischemic damage. So if you lesion one part of the serial pathway, the information doesn’t loop around anymore. XI. Long-term potentiation (LTP) [S11] a. Don’t worry about the wave forms just worry about the size of the synaptic response and whether they are bigger or smaller b. This is the first study that was done in vivo in rabbits. c. Used 2 stimulating electrodes that stimulated two separate inputs into the dentate gyrus d. One of the pathways was controlled and was stimulated once every 30 seconds and the response stayed stable e. Referring to before wave: so before and after, it didn’t change, it stayed the same size. Referring to after wave: this synaptic response got bigger and we’re recording the synaptic response in the dentate gyrus. It gets bigger here and why does it get bigger? Because they gave high frequency trains, a burst of AP to the stimulating electrode and now the AP comes down to synapse much faster so the response gets bigger and it stays bigger and it ultimately saturates. That makes sense because you only have a certain number of synapses they can only get to a certain size depending on the mechanism. f. The responses got bigger and stayed bigger for days and weeks in vivo so the animal has a completely changed hippocampus. This was really cool because no one had demonstrated a change in synapses that had lasted that long. g. To this day, this is the best model that we have. h. This experiment hasn’t been done in humans but this shows that hippocampus is actively involved in learning memory tasks and recalling. XII. Properties of LTP [S12] ***for this part of the lecture I tried to follow along with which graph he was referring to. He bounced around a lot but I tried my best to group everything with their respective graphs*** a. We have to learn a little about the properties of this graph. b. Think of Pavlov’s dog and you will remember this. c. Pavlov’s dog, we have pathways coming into hippocampus, associating information, and we have NMDA receptor (the molecular switch). d. Pavlov dog i. CS, the weak input, produces a small response. The teacher, the food, elicits a strong UCR. e. If we give a high frequency trained to a weak response, it doesn’t do anything because it is weak. There must be a threshold of activity before you can get plasticity. f. Referring to cooperativity graph: weak before/after no change. Now if you stimulate the weak at the same time you stimulate the strong, the strong potentiates and gets bigger and stays bigger, this is long lasting plasticity. Referring to associativity graph: But since you are doing this at the same time as the other, it makes the weak one stronger. You are associating information in those two pathways and this really happens. The strong has conditioned the weak, long term plasticity of the weak. g. The idea of these first two here (A & B) that there is some sort of threshold of activity, if not provided you don’t potentiate. But it may be provided by this one, telling this one to change, so there is some amount of activity and that relates to NMDA receptor. h. Referring to specificity graph: important because it satisfies Hebb’s postulate you need pre-synaptic and postsynaptic activity. You can stimulate the strong one all you want but if you don’t pair it with the US, then the US never learns. So we need to pair them and that is the same as Pavlov’s dog. i. If you don’t ring the bell, then they don’t learn to associate the bell with the food. j. This tells you that you need presynaptic activity and (now referring to graph B) you have post-synaptic activity that spreads down and influences the synapse. k. [SQ]: Explain difference between A and C on the figure. [A]: Referring to graph A- In any form of learning you need both stimuli. Referring to graph C- if this is the bell, you will never learn if you are not presenting it at the same time. If you keep ringing the bell and never give the meat, you never learn the association of salivation with the bell. So you allow these to go together to allow the graph C- pre and post is tricky. Graph A- the postsynaptic activity is due to the strong input that spreads down here and presynaptic activity is releasing glutatmate and you need to post-synaptic activity glutamate, graph B the reason you need that is… Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 4 of 7 XIII. Learning Objective #2 [S13] a. Discuss the characteristics that make NMDA receptors coincident detectors cable of initiating associative information storage (Pavlov’s dog) b. These are the required to activate NMDA receptors because that is the switch (continuing answer to question). XIV. Cellular mechanisms underlying LTP [S14] a. This is LTP. Here’s our synaptic response- we are given a trained high frequency input. We potentiate the response, it stays bigger. We worry about the induction- and how does the change happen. And then worry about why it stays big afterwards. During the high frequency train, something happens. But, then we go back to our normal stimulation, then it stays big. It remembers the train. XV. Excitatory synaptic transmission [S15] a. Illustrate - what goes on at these glutamate synapses in the brain. b. 2 types of post-synaptic receptors i. AMPA receptor – doesn’t really matter, not the NDMA receptor. ii. NDMA receptor 1. Remember-under normal condition-everyday resting membrane potential, NDMA does not participate in synaptic transmission, hardly at all if any. It’s the other receptor. 2. Here is the synaptic response, if you block the NDMA, it doesn’t change the synaptic response. Those receptors aren’t playing much of a role in the response. XVI. LTP depends specifically on NMDA receptor activation [S16] a. If block NDMA, at the time I give high frequency train, it completely blocks the plasticity, you don’t get LTP. i. You get a transient change, but it goes goes back to normal. b. Wash the blocker of, you get LTP. That tells you that, the NDMA is at the synapse, doesn’t do much until you give high frequency train is given. c. That’s where the idea that this is molecular plasticity switch. It turned on by high frequency stimulation, associative high frequency stimulation, it causes the synapse to change, and it turns back off again. XVII. What is special about NMDA receptors? [S17] a. Why does that happen? And how does it fit in with associative? b. Remember different types of channel- NDMA is a ligand-gated channel and also it needs voltage as well. i. It also needs voltage because Mg trapped in the channel under normal conditions. That’s why it doesn’t have a role in normal synaptic transmission. Mg has to be kicked out of the channel, so that post-synaptic depolarization kicks it out. ii. NDMA receptor is a closed channel, waiting for glutamate, glutamate opens the channel, as soon as it is open- Mg plugs it up, so it doesn’t play much of role. iii. But, if we give a lot of depolarization, this is our strong input now depolarizing that cell really strongly, it kicks the Mg out. Now, ions come in through that channel. XVIII. NMDA receptor: a molecular switch [S18] a. This is trying to put all of those together. This needs to make sense to you. Remember, Pavlov’s dog to begin with CS and US. This is represented by our weak input which is CS, and strong input as US. b. Hebb’s postulate, you need both conjoined pre-synaptic and post-synaptic activity. c. NDMA needs joined pre-synaptic and post-synaptic activity. It can explain everything- it can put it together. d. We call the NDMA co-incidence detector. i. If presence here at this synapse, well- its present at both that’s why they both can change. ii. But, if it present here (not sure where he’s pointing at), then it can detected pre-synaptic activity coming from here because that’s glutamate being released. It needs glutamate to open it. And it can detect the spread of depolarization from the strong input down the dendrite. So it spreads, it depolarizes and it kicks Mg out and it can be activated. e. It’s a co-incidence detector. It will not work if the two conditions are satisfied. f. So if I don’t stimulate the input, it doesn’t matter the how much depolarization spreads the dendrite, the channel will never open because there is no transmitter there. You need channel to be open, to get the ions to flow through. g. Again, if I stimulate this pathway, and provide glutatmate, it’s a weak input, doesn’t depolarize enough, so it never kicks Mg, so it doesn’t get activated. So both conditions satisfy this. h. At the molecular level, and the circuit level, so we understand quite a bit how these process could accounts for associate information storage. i. [sq]- is there Ca input? i. [A]- One of the peculiarities NDMA receptor is that they do flux in Ca. When you kick out Mg, the current is carried by Ca. And Ca does turn on various things and causes the changes to happen. j. [sq]- Something about the slide and pre-synaptic and post-synaptic on the diagram. Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 5 of 7 i. [A]Happens on the same dendrite. They are both pre-synaptic. They are both the synapse. We are only talking about what’s happening at the weak synapse. Think about p. dog, it’s the strong unconditioned input that trains the weak or conditioned input. k. Diagram on the board- This is our big synapse. A little synapse. This one releases glutamate, and this one we get lot of depolarization that spreads upwards, it can passively spread so this one is depolarized. The same thing happens here, this one satisfies itself because it is a strong input, so it has glutamate and depolarization and that’s why it potentiated anyway in an unassociated manner. l. But one of the ideas it has been shown, that it can happen with single input. So one idea is that now that the reason you see this potentiate as an unphysiological, we have never this massive input stimulated together to potentiate itself. It’s representative of an unconditioned input, which we don’t really know what it looks like. m. Depolarization and transmitter, and the key is NDMA receptor. n. If I ask questions- if you understand this diagram- this is the majority of what you need to know to understand NDMA and associative plasticity. You should be able to work yourself through this. o. [SQ] – Something about weak response and depolarization i. [A]: Weak input has glutamate, so the glutamate binds to the receptor, but it’s so weak t hat it doesn’t depolarize that part of the dendrite at all. p. [SQ]: If you block the NDMA receptor, what happens? i. [A]: If you don’t block the NDMA, you don’t get any plasticity happening at all. You stopped GLU from activating it. You still would depolarization, but preventing glutamate can’t bind to the NDMA receptor, which is the antagonist does. XIX. How does the NMDA receptor cause a change in synaptic strength? [S19] a. Ca is important. There are a lot of biochemical cascades. We don’t worry about any of those. Name your favorite Kinase or phosphatase and it’s involved. Someone has shown its involvement. XX. Synaptic transmission is unreliable [S20] a. Likewise, depending on exactly who does the experiment and their conditions, they are arguing why the synaptic response stays bigger. There are three ideas: i. You can more transmitter released, so bigger response. ii. You can have more receptors, or something change post-synaptically, so you have a bigger response. Or different sensitivity to the transmitter. iii. Or form new synapse. b. Still being argued about what happens after plasticity. So remember that’s the maintenance, we have before and after, so something had to change to make the response it stay bigger. The induction is the NDMA receptor, what happens when we induce the plasticity. XXI. Hippocampal “integrated circuit” [S21] a. Don’t remember all of this. Just flick through yourself if you want to see how people have encoded patterns through the hippocampal circuits. b. It looks like a circuit board, if you reduce the hippocampus to its connections. i. It has parallel inputs which are axons. Perpendicular, you have dendrites poking down. c. People have looked at this as a circuit board, with synapses turning on or off. d. We know that you store patterns of information in associative manner through circuit boards like this. XXII. Associative pattern storage [S22] a. No questions from this slide, it’s just added for completeness. b. Illustrate- there are synapses (yellow), if you have associative input from both these pathways, it will cause plasticity. You can work yourself through this, and show plastic changes, different patterns, and if you play them back it will recall the patterns. information from both c. Throw it in trash and not worry about it too much. Want you to remember everything else more. XXIII. Learning Objective #3 [S23] a. NDMA receptors, associated information, two requirements: pre-synaptic and post-synaptic activity. b. Everyone was thrilled with that because there was a molecular mechanism that takes place in hippocampus that may models associative learning. But does it actually underlie associative learning. Its phenomena. I am electrically stimulating those inputs, so producing this effect. Is there further evidence that’s underlying learning and memory? c. There is actually more recent information, but most of holds. XXIV. NMDA receptor-dependent learning [S24] a. Spatial recall in humans, this is spatial recall in rats. b. This is a learning task commonly used now. There is water maze, big circular tank of water that is opaque (so can’t see through it). The tank is arranged in a room with lots of visual cues around it. This is visual spatial memory task. The animal needs associate different parts of the tank with spatial cues in the room. If you remove the cues, then it doesn’t learn the task. Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 6 of 7 c. It is associating visual information to location. That’s associate information. Declarative memory involves the hippocampus. If you take out the hippocampus, then it will not learn the spatial tasks. If you take the human hippocampus, then it will not learn spatial task or convert from short to long-term memory. d. If you train the animal, put the animal in the tank and train it to find the platform that is submerged so it can’t see the platform. The water is opaque. By trial and error, it swims around, and it wants to get it out, so it looks for the platform. They don’t like swimming indefinitely. Give it multiple learning trials; it will get faster and faster remembering where it is. Same location, same visual cues. By the end of 4 or 5 trials it will just swim directly to where it thinks the platform is. e. You do a probe trial sometime later, you remove the platform. i. If the animal has learned the task, it show swim to the spot and look around for the platform. It is shown on the slide. ii. If it hasn’t learned the task, then it will spent equal amount in all of these quadrants looking for the platform. Some people can say that it’s a smarter animal, because if it’s not there, then it’s somewhere else. However, that’s not the task is interpreted. iii. If it has learned, then it will spend time in the right quadrant. If not, it spends equal time in all quadrants of the pool. iv. So if you block the NDMA and fuse it into the hippocampus, it doesn’t learn the task. One piece of evidence. The NDMA receptor must be active. The NDMA does not affect its swimming or locomotion. Its visual acuity is fine. It can still do all of those things, it just can’t remember. XXV. LTP and learning [S25] a. It brings together of what we know. b. There is limited storage in the hippocampus. The memories don’t stay their forever; they have to go somewhere else. c. You should be able to block learning by saturated all the synapses. They implanted electrodes chronically in the animals. i. LTP-induce everyday in those inputs until no more LTP. ii. If the theory is right, that you must be able to the synapses undergo LTP for the animal to learn, so it won’t learn anymore once you have saturate the synapses. Maximally potentiate. d. It’s the same water maze. e. Here LTP everyday for two weeks and saturate LTP, you can never get a bigger response. It you try to get the animal to learn the task now, it can’t learn it. It will go around all over to find the platform. f. If you let the LTP decay over a number of weeks. It tells you that’s it’s not permanent. You want to free up the hippocampus, that’s good so you it can process new information so it can put it somewhere else for permanent storage. If you the LTP decay, and then re-teach the animal a new spatial location it will happily learn it now, and spend it’s time looking for the platform in the right quadrant of the pool. g. The hippocampus seems to require that the synapses undergo potentiation, otherwise it doesn’t learn. XXVI. Diffuse storage in cortex? [S26] a. People wonder how/where memories are stored for years. Thinkers- David Marr from a long time. b. We have this understanding that we know something that’s going on in the hippocampus because of multiple reasons. i. We know some of the physiology, molecular and cellular physiology that has the right properties that accounts for the associative learning. c. In humans, if you damage hippocampus, we affect the conversion of short to long-term memory. d. On Wednesday you will hear, if you have damage here, people have trouble with new long-term memories with Alzheimer’s disease. One of the things people will report with this disease that people will get lost. Associate the spatial encoding with the hippocampus. ie. These patients try to visit someone and have a terrible time getting to there. This connects the spatial information and coding with the hippocampus. e. Hippocampus is important for spatial task and memory and generalized role of converting short to long term memory. It ends up somewhere else in the cortex. f. Memories are diffusely stored. Memories have different components just like jigsaw puzzles. It might have visual and auditory information. Those pieces of information might be associated with higher order visual or auditory cortex. You lose face recognization, you forget faces if you have damage to what pathway in the visual stream? In the temporal cortex / temporal lobe. g. Store memories diffusely, and the reason why storing them associately, because you have want associate them with each other, you think of one aspect of a memory will recall this other information. h. This is theory, might be a little evidence for it. i. This represents your cortex. Different parts of the cortex lighting up coincidently when you are learning. You might visual, olfactory information. It can be different parts of your brain. Neuro: 1:00-2:00 Scribe: Sally Hamissou / Sunita Jagani Monday, March 16, 2009 Proof: Dilly Willy / Dylan Vaught Dr. Lester Synaptic Plasticity Page 7 of 7 j. One idea - Because they act together, the connections between the cortex are strengthened. This area and this area is now wired more strongly, changing wiring. It could be anatomical or physiological by a LTP like mechanism. i. Maybe there are new synapses formed. We have associated these. ii. It may have taken sometime to recall the information and thought about several times. It’s not just a one trial learning in this case. iii. But the advantage is that, if you get olfactory information coming in, and maybe a little more than just olfactory. Like here is a pneumonic coming in, it pulls out the other associated bits of information. Pneumonic is helping us remember. You still have to remember pneumonic what it was encoding for, but the pneumonic is all you need to start to pull the information down. iv. That is a stretch for analogy. Don’t mind you making these stretches-if helps you remember it. v. End [52:58]