 Okay, let's get started with a new series of three lectures, here they are, on learning and memory. So we finished sensory systems now, you know everything about how information gets into the brain and now we're going to turn to what your brain then does with that in order to consolidate it, store it and use it for the future. So there's three chapters in the book here that cover that and as with all the other lectures it's going to be a lot of material, it's kind of similar to maybe the vision lectures to some extent in the sense that this will be kind of an overview of memory systems and then there'll be some of the synaptic circuitry that underlies memories and then there'll be other forms of memory and memory modulation in the next lecture. So here they all are with as usual the some of the main take home points to help you anchor the lectures as you get them. Let's see, any announcements that there were, oh there was one. So next week Thursday in discussion section you have like I guess learning and memory then there is Thanksgiving and then there used to be no discussion section in the week after Thanksgiving but now there is one. So a discussion section, I think the original syllabus there was nothing listed or something. So there will be a discussion section in the Thursday after Thanksgiving on I guess illnesses of the brain. Any other questions, any logistical questions or anything from the class? Okay so as usual try to take a look at the PDFs and try to read the chapters in the book before the upcoming lectures. So here's the topic of today, here's a question that you guys might want to map onto analogous questions that we've asked in the past with respect to sensory systems. It was quite easy in the case of vision and hearing. It was harder in the case of somatosensation. Does anybody want to take a stab at answering, giving an answer to the question of what is memory? What would you say memory is? Yes. Okay great so that was a straightforward mapping onto the answers we had in the past and certainly it's in part correct. So the answer was to know what is where by remembering. It shows you that memory is active and in order to remember something you need to often employ very strategic things so if you experience this first time all the time you need to remember things for an exam, you don't just pop into your head you have to try and retrieve them. They're in there but you might not be able to get them out of your head. And then knowing what is where is certainly part of it and that's actually a big part of what we'll talk about in today's lecture in relation to declarative memory which is thought to be memory that binds together different types of information about events like what and where and in the case of declarative memory episodic memory also when. So you would indeed embellish what you just said and say to know what was where when and to do that through recollection. Let's just think about that for a second more and see if anybody wants to come up with a further answer because if you think about it the way we just said it so that the memory is to know what is where and when it happened by remembering it. If you just stop there you would say so what's the function of that? So I think about the past and I can reminisce about something that happened at a certain place at a certain time so what use is that? It already happened, there's stuff in the past. What use is thinking about the past? It happened, I have no control over it. So is there a more functional answer that somebody would like to take a stab at? Yes. Great, okay. So you could embellish the initial answer and then you could say the mechanism is indeed to know what was where when by recollecting it but then to use it for something and you don't want to use it in order to think about the past like I said the past happened. So you would have some answer that says memory is the ability to recollect information from the past in order to guide actions into the future. So the point of memory is to plan for the future by learning from the past. So if you have some answer like that that for instance you could embellish on a problem set or exam that would be good to think about. Okay, so we've answered the question partially or given you hints for the direction in which the answer might lie, I should say the answer to this question what is memory? I think the answers we just got are actually very good but it's more difficult than in the case of vision and in the case of the auditory system for the same reason it was difficult in the case of the somatosensory system which is that there's not one kind of memory. So there are many different types of memory. The one that comes to mind most easily is this type here, declarative memory which is recollecting events that you can consciously re-experience in our own case but there are many other types of memory that are not like that. You already had a ride a bicycle, Pavlovian fear conditioning, so it's many many different kinds of things and that's one reason it's a little more difficult to come up with an answer to this question but certainly one thing that unites them is to be able to use information from things that happened in the past to guide future action. The two big types of memory we'll talk about declarative which is sort of everything you can tell me about and what the person on the street would normally mean by memory and everything else which is like how to play chess, how to ride a bicycle, all kinds of memory that are not things you can tell me about but they're more things that you've learned how to do rather than information that you can recollect and tell me about. In addition to those that heterogeneity in different types of memory there is heterogeneity other different types of phases of memory in terms of the mechanism and typically these have been divided into three that's not a strict partition but there's initial encoding you have to get stuff into the brain there's consolidation often over quite some time you have to make sure you don't forget it and you get stabilized often embellished sometimes you have false memories there's lots of complicated stuff going on over time and then eventually you have to get it back out again and retrieve it or recollect it so those are and those are all distinct stages of processing so that also makes it more complicated. So then we'll talk about those we'll talk about types of declarative memory and some of the brain systems and then on Monday Henry Lester will tell you about the cellular and synaptic basis of memory what do we know about the detailed cellular mechanisms that implement some of these in many cases psychological level processes and then next week Wednesday we'll talk about non declarative memory and also memory modulation. So there's several core puzzles to think about thinking about memory the two main ones are here so one and they're kind of complements of one another so one is how do you get changes encoded in the brain so you might and you might immediately think of multiple mechanisms and there are multiple mechanisms many of those map onto multiple phases in time so you might think well if I just keep a neuron keep a bunch of neurons active and they keep firing in some kind of reverberatory activity that's memory I would have some representation and as long as it's active in the brain in the sense of neurons continuing to fire after a stimulus has disappeared that's memory you might think that that wouldn't be a very efficient way to store all of your memories and indeed it's not because I have to keep all your neurons firing for everything that you ever experienced so in addition to that you might say well I can turn them off but I'm going to have some other changes for instance actual ultra structural changes in the connections that they make with one another in the genes that they can transcribe and to some extent those processes map onto short kinds of memory like working memory that you can think about actively and long-term memory that decades later you can recollect so it's many different kinds of things but that's one challenge how do you do that how do you encode those changes in the brain and then if you do that it raises a corresponding problem about how you can hang on to anything as stable if your brain is changing all the time because of all the memories being encoded then how do you how do you stabilize anything if your brain is changing all the time so you need to have very complicated mechanisms on the one hand to separate from one another and avoid interference between different memories and to stabilize them and on the other hand to make sure that those that that you don't have too many memories but can you need to have filters filters in in place you don't want to remember everything although as I'll show you and allude to in just a couple of slides there are people who seem to remember almost everything curiously enough okay in so in terms of those filters there are a bunch of constraints many of them actually fairly innate in terms of what you can learn and how you learn about it and you all know this it's much easier for you to learn in this class and it would be for Henry Lester or myself if we didn't know the material because our brains are older it's much more difficult once you're out of puberty to learn a new language so there are certain windows where the brain is is more open to learning about certain kinds of stimuli and that applies to lots of different things even if you look at very basic kinds of conditioning in animals learning associations between stimuli isn't arbitrary it's much more difficult for a possible for animals to learn some things than to learn other things so there's a lot of filters into place already that predispose the brain to be able to learn certain things rather than others so language is one example of that okay so we had this here's the already answered this question here's the Wikipedia entry for it I don't know if that adds much it does point out that as originally conceived memory and of course as historically mostly studied memory and learning and memory have been studied behaviorally in psychology so it's only much more recent that we've looked at the underlying neurobiology so you should keep those separate a lot of the terms and concepts derived from psychology and then it's to some extent a separate question or you at least you want to keep it separate in your head in terms of how that relates to the neurobiology for instance short-term versus long-term memory those have specific definitions psychologically but it's not all clear how these those relate to those same terms short-term versus long-term yours used in neurobiology they would have different different definitions this is one of the main psychological guys this funny-looking person up here and the tumbling is a very famous psychologist who came up or was one of the many people that has tried to articulate what at least for psychologists and also for many lay people is sort of the hallmark of memory and again in not everybody's but in many psychologists theories is unique to human memory so he has this somewhat fanciful quote here about evolution building a time machine in our brain and episode the main one of the main puzzles one of the main things that people have thought is unique to humans is to be able volitionally to re-experience events that are not in the here and now the idea would be that of course animals learn animals have memories but animals are sort of stuck to whatever it is that their senses provide that determines the content of their conscious experience the conscious of what's in front of them of the world around them you need not be and most of the time you're not your day dreaming and you're drifting off you're all conscious of what's in front of you but you're thinking about things that could happen in the future that happened in the past and so that ability to zoom around in time seems to be something that's extremely difficult to explain it's been very difficult for obvious reasons to find clear evidence for it and animals other than humans and it depends on a particular brain system that that we now know quite a quite a bit about so that's that's one quote here okay so what is that brain system so here is the is one taxonomy of memory and this is not a taxonomy that everyone would endorse it's kind of course but at least at the courses level up here people agree with this that there are two so this is one main thing that you should know there are two broad types of memory declarative also called relational memory and everything else declarative has been studied fairly well and related to a particular part of the brain the hippocampus and other structures close to it in the medial temporal lobe and that's been shown in humans it's been shown in animals and it's very good evidence there we know a lot now about the mechanisms etc non declarative memory is very heterogeneous and it's a whole bunch of different things some of them we know about a fair amount like Pavlovian fear conditioning that's sort of over here and depends on structures like the amygdala and some of them a lot less so it's a heterogeneous batch of things what distinguishes declarative memory intuitively it's everything that you can tell me about so it's if I asked you tell me some you know what's the capital of France and you would say Paris that would be an example of a semantic declarative memory or I could ask you tell me what you had for breakfast this morning or tell me what you did yesterday and that would be an example of declarative episodic memory so it's facts and events that you can recollect these things are all different than that they're not things you can tell me about it's like learning to ride a bicycle play chess or have some automatic response to a condition stimulus any questions about this basic distinction between the clarity of which is also a couple of things but they're all kind of similar to one another that depends on one brain system and non declarative which is a heterogeneous mix of everything that's not declarative any questions about that distinction okay so those and we're gonna talk about this first one here today and then focus on this one next Wednesday so let's talk about the temple components that I alluded to so you have encoding or acquisition and there's lots of filters and things that modulate this that's I call it sub study so for instance the more recent something is the better you remember it if you rehearse something the better you remember it if something is associated with strong arousal and attention the better you remember it all the things that you try to do when you encode information when you're studying for a class for instance right so it's all of those things it's not like just taking a picture of the world and then you're done so there's very active mechanisms that prioritize information that gets access to consolidation so there's stuff here at the beginning attention arousal and so forth then what you have is a whole bunch of processes which is whether these different terms in here that stabilize that memory so it becomes temporally durable so you can think of something right now you can be reading something in your textbook an hour later it's gone so you haven't consolidated it so you need this consolidation mechanism many many things play a role here and it takes place over some long duration minutes to weeks to years so it's and as it does so it becomes stabilized it becomes embellished and it becomes often abstracted and incorporated with other things so many of your autobiographical episodic memories become converted into more abstract semantic memories that are facts so for instance you know that Paris is the capital of France but if I asked you well give me the specific the specifics of how you know that when exactly did you learn that where did you read that give me that specific autobiographical memory that's lost so you were I don't know you know I heard it multiple times I read it in a book and somebody told me when I was little and you know whatever a whole bunch of things but now you've consolidated that into just a big more abstract aggregate you know that as a fact but you don't know how you know it you don't know how you how it how it got in other things so other what we'll take a look briefly on Wednesday next Wednesday it's important to point out there are many mechanisms here that modulate this so even once you've got once you've studied the textbook and you're starting to consolidate something it can get lost or it can get embellished so if you have other things that come in that interfere that's not good if you don't sleep that's not good sleep is actually one of the main one of the big roles of sleep does many things but one big role is to stabilize and consolidate memories and people have studied that so if you prevent people from sleeping and otherwise have the same temporal duration if you have sleep it will help consolidate your memories and then there is also of course some loss and embellishment which is probably not indicated here so memories can become false you can have false memories over time they can become repressed you can have a lot of modulation here over time so that's consolidation and then finally if you wanted to do something with it you would recall it every time you recall a memory of course it becomes a stimulus in its own right and so when you recall something it can be reencoded and then reconsolidated and so you can have reconciliation here's one scheme for how this works in the abstract so if you see a car or some picture in your book your visual courtesies would have a representation of that so what's schematized that's schematized up here so remember we had all these different maps that map the color the direction of motion and so on in higher-level visual courtesies would have object recognition of this car and its context this would be represented in sensory courtesies so that's your percept and presumably a big part of the content of your conscious visual experience of seeing a car then there would be higher level regions that encode conjunctions between that the context in which the car occurred when it happened and so on and this would be not just a single step but a layered hierarchy and then once you have that the idea is that these higher-order regions could sort of serve to reenact or simulate the original car so you would take a look at this car if you remember what it looks like I could ask you tomorrow form a visual image of the car and you can do that by retroactivating the same visual cortical areas that were initially activated when you saw the car so and this this does happen this way so people have looked at this for instance with with fMRI studies that in this particular example of forming a visual image on the basis of memory for something that you saw before you replay it in reverse and that requires having these high-level regions that can sort of serve as pointers or recipes to reconstruct the same visual pattern in cortical regions that you would have got when you originally saw the car okay now how do you get that how do you trigger that and of course this is extremely complicated and often fails you know that you know something but it's often very difficult to get at it the two main mechanisms for retrieving memories are these two here one is recognition memory so that's retrieval triggered by the stimulus or something very similar to it so when they go to the parking lot and see a car similar to my silver Honda fit of which there seem to be almost every car looks similar to mine so never find it I know that triggers a recognition and I recognize it as as my car so recognizing recognition memory is one of the simplest forms of retrieving memory you recognize something as familiar because you can match it with the representation that was there in memory you see it again and it matches recall is is harder so recall is also retrieval but it's not triggered by seeing the same stimulus but either spontaneous or by some symbolic queue so I could ask you just verbally think you have described to me your car and that's harder so because there you have to go from some very symbolic tag that doesn't yet give you much of the similarity structure of the representation you want to get at and do the whole retroactivation and imagine seeing the car but so those two are the main forms of retrieving memories recognition just kind of like a matching and recollection which is real synthesis any questions about those they're all clear to people psychologically okay here's some other terms to notice and coding that we talked about consolidation talked about retrieval and the two types of recognition or recall naturally let me just go straight to working memory here so this slide you need to know in detail and it's well embellish a bit on it so you have things coming in you have your eyes and your ears open and you have sensory percepts coming in and then you can act on that there is a part of memory in your brain called short-term memory psychologically or working memory it's pretty a better term which stores those things it has specific features it corresponds to what it is that you're conscious of when you think about something it has a very limited capacity and it tends to be fairly ephemeral so if I give you a bunch of numbers four three six eight nine one three two nine six four right if you can hear him and now ask you okay give him back to me when you do that with people when they're paying attention they can give back about seven or so but not 20 normally so there's a limit seems to be around seven depending on how you chunk the information that's coming in quite limited way more limited than your long-term and everything you know in your long-term memory and it lasts about a minute or so so this is a very specific kind of memory it's an essential initial buffer before you can encode anything into long-term memory so you need to get you need to see it or hear it and get it into your brain then you need to think about it and have loaded into working memory which is this temporary limited capacity buffer and only then can it be transferred via the hippocampal formation into long-term memory stores and long-term memory is everything that you would know once you have consolidated it into long-term memory and that's very different that stuff that can be there for a lifetime it doesn't have just a one minute half-life and its capacity as far as we know is unbounded in humans so it has a huge capacity everything that you could ever remember and then of course the trick is you need to get it back out to get it back out you have to reload it back into working memory so you can think about it and then you can tell me about it or act on it okay so those are the two basic divisions short-term memory long-term memory short-term as a last about a minute or so and has a capacity of about seven pieces of information long-term has no bound on time or on capacity as far as we know that makes sense to people this here working memory is known to depend a lot on mechanisms in the frontal cortex and transferring this into long-term memory depends on the structure we'll take a look at in a minute which is the hippocampal formation and then there's lots and as you would imagine there are lots and lots of modulations that can facilitate or block each of these processes the most dramatic evidence for dissociations between these we'll take a look at this in a minute but just to tell you is if you have damage to particular parts of the brain you can impair one or the other of these so for instance you can have patients that have damage to the hippocampus and their short their working memory is perfectly fine but they can't transfer that any of that into long-term memory there's another form of memory that psychologists like to use this is essentially just at the encoding stage so what people call iconic memory is very short sensory trace before you think about it before it's loaded into working memory working memory as I mentioned just like up to about a minute half a minute to a minute they're different aspects of it ones that the best one best understood ones that people have studied is visual spatial working memory so if you can just seeing visual patterns without encoding them into language and encoding things into language and rehearsing that in your head so if I give you something to remember you have to generally convert it to one of those two things it's extremely difficult to do anything other than that so for instance if I give you a whole bunch of odors and ask you to keep thinking about those that tends to be impossible unless you put a verbal label on them in which case you're converting them to the phonological loop so you usually have to think about things and hold them in working memory either by rehearsing them as words that you just have in a little verbal loop in your head or as something visual like a pattern or a movie or something that need not be verbal those seem to be the main ones then long term memory serve anything longer than working memory as I mentioned these have different terms generally in neurobiology so they're also short term and long term memory mechanisms the main difference there is that typically by long term people mean something that depends on gene transcription and short term something that doesn't you don't quite map onto these same time scales as the psychological categories so how are these here's one scheme for how memory relates to what it is that you're conscious of so initially so here these three time scales of memory that we just spoke about very fast iconic memory when you just see something but you're not thinking about it working memory is stuff you can rehearse but without rehearsal it decays after about 30 40 seconds you can only hold a limited number in there long-term memory is not stuff that you're thinking about it stuff that you have stored permanently with a very large capacity so that's what's shown here so anytime you experience anything it's there for a short duration sort of the time span of your conscious experience of it that's iconic memory if you start thinking about that and holding it in memory even after it's gone that active thinking about it is working memory but you can't do that for too many things and then everything else that's really long-term memory that you have to retrieve stuff out of for it to become conscious is long-term memory okay so I already mentioned working memory has a span of as a capacity around seven items here's an example of iconic memory it probably won't work because I don't have this set up for the time to be right but George Spurling did an experiment that illustrates the distinction between iconic and working memory so the experiment is this you would you would look at a screen and they would flash up this and then they would say report back to me all the numbers and typically people aren't very good at that they can only do see three four numbers a small number of numbers they make a lot of errors when you when they're asked that question but you can do exactly the same experiment so again you flash it up but right after flashing after the stimulus is off the screen at the outside of the stimulus you cue people to think about a particular row so it looks like this now you have those come up and then you would see better timing than I've done here something like this if you do that people are able to report that particular row very well even though the cue for what to pay attention to is only after the offset of the visual stimulus so that shows you that even after the stimulus is gone from from from the screen there is still some short-duration trace that presumably has to do with latencies in the retina latencies in responses of neurons in visual cortex there's still something there that the brain can use in terms of a visual representation even if there's no stimulus on the screen that's iconic memory so this example shows you how if you give a particular cue somebody can use that ephemeral sort of one to two second trace of sensory memory and iconic memory to transfer it to working memory here's a more entertaining example so this is from a Japanese researcher who works with chimpanzees and these chimpanzees are trained have been trained to push on a touchscreen here these numbers in ascending numerical order okay I guess depending on your priors here this could be impressive or not at any rate each time they go down to get a little raisin or something which is the only reason that they're doing this but so they can do these numbers they can recognize after a lot of training they can recognize what these numbers are and push them in ascending order okay it doesn't have anything to do with memory the experiment that he did was to now show that these chimpanzees have a remarkable seem to have a remarkable iconic visual memory by masking the numbers right after they up there up so now the experiment is this one which is very hard so it's the same task except as soon as the numbers come up they're mass but the idea is that the chimpanzee can retain where they are it's chimpanzees doing this correctly in all these trials presumably because the chimpanzee has a very much better iconic memory than you or I do and this is actually this is the reference to the paper down here this is one of the sort of main psychological theories that people have about the types of memory between animals like chimps and us that in our case our iconic memory for specific instances is actually not that good and what we tend to do is to try and abstract from that whereas chimps pay attention to all of the details and encode that rather than abstracting from that but so this but the point is this just keeps your hands on field for what the chimp was using here was iconic memory okay there are many things that improve memory and psychologists have studied this in in great detail the more recent something is the more easy it is to remember that's not too hard to figure out if it's in working memory that's certainly one case even in long-term memory that tends to be a decay active forgetting interference with other memories all of those processes are minimized if something is very recent if you pay attention to it this augments encoding and consolidation of memories emotion has been studied a lot in relation to traumatic memories both of these mechanisms attention to emotion are probably similar and people have looked at the particular chemicals like norepinephrine that is released when you're emotionally aroused that seem to modulate memory encoding if you in general if you ask people to just tell you about autobiographical memories they will they will be able to remember emotional events in their lives much better and less emotional events in their lives they're encoded much more strongly they can this can also go in the opposite direction if you have traumatic memories in which case that could be repressed in some cases etc but so emotion is a big modulator of of memories repetition is of course one so what happens in repetition is that you keep holding something and working memory working memory decays after about 30 seconds if you don't rehearse something but you can actively keep rehearsing a bunch of phone numbers for as long as you like and each time you're as long as you're thinking about it it is gradually being offloaded and consolidated into long-term memory so if you keep repeating it you will give long-term memory much better chance to consolidate that that memory and then it's elaborated distinctiveness of the memories is important and as I mentioned sleep is quite important people have looked at this been tricky to do these experiments but there is unambiguous evidence but so far surprisingly narrow specific evidence that at least some forms of memory in humans and other animals but in humans depend on sleep and actually depend on particular stages of sleep particular ratios of rent to non-rem sleep and so on so sleep serves an important role in memory consolidation is the only factoid to know here's another factoid just to mention this this is a study there's several papers here's just one from researchers at UC Irvine Jim McGaw and colleagues and with the somewhat dry plot here shows is the ability of a bunch of people that have sort of extremely good memory which are the open bars to remember particular dates and these are various kinds of things like the day of the week so you would say something like January 7th 1963 and for one of these people they could say okay that was a Tuesday and I remember reading the newspaper and this and this happened it would be a verifiable event and they could tell you lots about their autobiography and so on by comparison control subjects generally can't especially if you verify them so there are people like this that have been studied if you're interested you can look at this paper and others for the same group at UC Irvine that seem to remember everything that happened on every day of their lives basically so there that seems to be a genuine phenomenon doesn't have any good explanation at this point and sadly it doesn't seem to help the people either they're not exceptional people they're often just normal people with normal jobs that happen to be able to remember everything but it's a striking illustration of how little we know about memory and also about the apparently unbounded capacity of long term memory it really seems as though these people just can replay any date in their lives which is a lot of information there on the negative side there are many things that compromise memory you'll hear about Alzheimer's disease and some of the later lectures normal aging compromises memory in each of these cases we know something about the particular brain systems that are involved and then there are various other diseases encephalitis alcoholism and specific drugs like valium which acts on GABA A receptors and other drugs that act on the acetylcholine neurotransmission so this particular neurotransmitter systems and there's diseases that give us insight into some of the brain mechanisms so what are those well there's a lot of different brain regions involved the one we'll take a look at in just a minute by far the one we know the most about for declarative memory are structures in the medial temporal lobe but then in addition to that actually everything you've heard about everything we've looked about so far in sensory systems does play a role in memory so they all play a role but the medial temporal lobe is most critical in binding all of these together so there's a bunch of systems there in cortex that subserve declarative memory and then that's modulated by all these other structures that have to do with signal to noise in terms of how memories might interfere with one another with strategies for how to retrieve memories when you think about them so there's lots of sort of modulatory systems in these from these structures that are shown at the bottom here that can interact with this medial temporal lobe memory system which involves interactions between medial temporal lobe and the rest of cortex that's responsible for declarative memory so what do we know about that well this the main knowledge started with one patient called HM who had epilepsy and for his and his epilepsy originated in this region of the medial temporal lobe including the hippocampus so neurosurgeons came in and they removed bilaterally on both sides of the brain the hippocampal formation and surrounding cortex based with the medial temporal lobe in this patient HM after the surgery so actually let me take a look here it's a little hard to see but here is the hippocampus that's been lesioned actually this is pretty clear here here in this scan these regions up here these white ones here and these T2 weighted scans of an MRI image show the regions in this patient's HM's brain that were lesioned so there was a fair amount known about roughly the region that was lesioned there's a lot more known since he passed away and people sectioned his brain down at UCSD there's actually a video you can watch you off this brain being sliced in this block here so people did postmortem histology and they know exactly now which parts of his of his brain were lesioned so he had damage to the hippocampus and some other parts of the medial temporal lobe that resulted in a very specific impairment that you need to know so here is where the surgery took place that's the time of lesion to the medial temporal lobe so very old memories from his childhood he can remember so that's there yet that's stored and he seems to be able to recollect that as you get closer and closer to the time of this lesion he remembers less and less so the name for this is this is a graded retrograde amnesia so it's an amnesia it's impairment in declarative memory retrograde means it's from memory prior to some manipulation this lesion and it's graded so what this shows you is that the medial temporal lobe hippocampus is important for consolidating information from the past so this is stuff that happened in the past and then you lesion the hippocampus and it produces the amnesia so this means that the hippocampus must still be important even after something happened for helping to consolidate it but that role becomes less and less important the more remote the memory is so if it's just one minute before the lesion and you do the lesion then you wouldn't remember anything if it's like an hour the role of the hippocampus would be less critical etc so there's a time-dependent role for the hippocampus in consolidation which should make intuitive sense to you the more you consolidate it the more stabilized the memory becomes and the memories themselves then become independent of the hippocampus as such going forward it's as you would expect so going forward nothing can be consolidated because the hippocampus is critical for that initial consolidation for transferring information from working memory representations into long-term memory so there's a complete antrograde amnesia so you can't learn anything new and you remember things from the past differentially well such that the closer they get to the lesion they the worse his memory are it's that's shown here maybe a bit hard to see but so here's just a one original old experiment if you show him pictures of famous faces actors politicians etc here's a comparison control subject in invisible yellow at the top here's H M so his lesion was in here and you can see that if you go remotely in the 1940s he remembers all those people he can recognize the faces as you get closer to the time of lesion there's this graded retrograde amnesia and anything forward any new faces he hasn't consolidated at all and he can't recognize them any questions about that syndrome that's produced by lesions of the hippocampus a graded retrograde amnesia together with a complete antrograde amnesia what is spared is everything that's non declarative so this is one of the key pieces of evidence that shows the distinction between those two big forms like a lot initially psychologically defined forms of memory so he can learn you can learn non declarative memories just fine there's no anti-grade amnesia for non declarative memories so for instance if you ask him to learn something he's never done to do a little hard to see here mirror tracing you can learn to write his name or draw things while watching what he draws in a mirror okay so normally if you do this you go the wrong way it's pretty hard if you keep practicing you get quite good at this and he gets quite good so his that's what's plotted down here and he retains that knowledge same thing for any other kind of motor memory same thing for Pavlovian fear conditioning all these different memories that are non declarative seem to be both learned and retained normally there's no amnesia either retrograde or anti-grade so this seems to show that the hippocampus plays a selective role in the encoding of the initial consolidation of declarative memories any questions about that part so let's take a look at this picture of the brain that we had before and see where this fits in the overall scheme of things you've seen this a bunch of times now so you would see something and this is as you can see not HMS brain or human brain but a monkey brain and which is schematized this but if you see something there would be visual representations down here in temple cortex and then you would act on those in this particular example here the monkey would push a button depending on what it sees depending on frontal lobe mechanisms in between here is this is the medial temporal lobe and this so there's a whole hierarchy of cortices and then the hippocampus that serves this memory function for binding together these representations it's a bit overwhelming here but it's illustrated here this is actually from a person who used to be here at Caltech David Van Essen together with Dan Feldman you've seen this before so here are your visual processing streams that start in the retina the parvo and the magno visual processing streams is all the different visual areas you remember we saw picture of all the different colors of visual cortex that serve different functions these lines denote connections between all these regions that people have figured out and sort of at the apex of this hierarchy is ER which stands for inter rhino cortex and the hippocampus HC up here so all of this information not just from vision but you could draw analogous diagrams for auditory systems metasensory system these all funnel into cortex in the medial temporal lobe that then conserved to bind together and to consolidate representations for those and you find analogous systems that people have studied in primates in rats across species and I can see I need to accelerate a bit here to finish this off you will hear more on Monday about the molecular mechanisms on this for this but so just to schematize it again you have these association cortices these are higher-order representations of what you've just experienced out there in the world neurons firing in these regions once you've seen something would be an imp would implement iconic memory and if you think about it and rehearse it in working memory then some of this would be linked to phonological loop or visual spatial scratch pad mechanisms that depend on the frontal lobe but this information these representations of what you experience feed into these cortices here in medial temporal lobe and eventually into the hippocampus and then there are mechanisms in the hippocampus that are showing this blown-up version here that are quite well understood at the cellular level that stabilize those associations between all of these different patterns so that you can bind together a memory and reconstitute it and replay it when you recollect it and as I mentioned those consist of different mechanisms there's there's some mechanisms that are relatively short-term and again this does is not the same short-term sense psychologically but short-term in terms of the the neurobiology which means that there are changes in receptors phosphorylation of receptors efficiency of synaptic transmission that is independent of gene transcription and then there are long-term mechanisms that depend on transcription factors a new proteins being made and on longer-term changes happening like insertion of receptors and actual ultra structural changes like making new synapses I think this is pretty much the same thing here and finally one thing worth pointing out is that as you heard in the development lecture in addition to all of these changes there are in fact new neurons that are born in your hippocampus and those also play some role in memory that's not very well-defined but it it's clear that they do play a role so you have multiple mechanisms in this brain region some having to do just with plasticity add a synapse in terms of just potentiating synaptic transmission some longer-term in terms of actual changes in gene transcription ultra structural changes and indeed birth of new neurons that all contribute to the memory function of the hippocampus most of what we know about the detailed mechanisms in the hippocampus come not from people but from animals and so one big question is how would you test this so everything I've talked to you about so far all depends on sort of conscious recollection language how would you test declarative memory how would you test hippocampal dependent memory in animals what do you find if you leave in the hippocampus in animals well it's not that they can't tell you about facts anymore because they couldn't tell you about facts in the first place what they can't do is something that's similar they also don't seem to be able to bind together information that is stored in the hippocampal dependent way and the way that people have studied that I'll just go straight to this year is in the so-called Morris water mace so if you take a hapless rat here the task that its brain has to perform is to bind together information about the spatial location of some object so if you have it zoom around it can swim around in this milky bath there's a submerged platform here it would like to go to but it doesn't know where it is so we put the rat in zooms around it really hates swimming around eventually it finds the platform do that a whole bunch of times and eventually after many trials it makes the beeline to the platform it has learned the spatial location of the platform how has it learned that you can't see the platform it's underwater the only way under the milk the only way it can learn with a platform is is by integrating spatial information of a bunch of things on the walls etc with its own body location to figure out where this is spatially located so this is that one test that people have developed in animals and one that seems to many people to be the most analogous at least in rodents here to this kind of declarative memory which is spatial memory like declarative memory we have to bind together information from many different sensory representations into a memory when something happened where it happened what was there same thing here the animal has to bind together information about many different spatial cues and its own body location to figure out where something is located in space if you manipulate this experimentally so this would be sort of much more precise versions of what happened to H M in in the human case in a mouse so you take a mouse and you put it in this Morris water maze and you can find that normally that's shown up here the mouse will go over to the quadrant where the platform is and has learned this if you do if you lesion the hippocampus it will not do that and it will zoom around like this if you do something more precise than that if you inject drugs into the hippocampus that interfere with the molecular mechanisms for memory in the hippocampus that prevents mechanisms like long-term potentiation block certain reset glutamate receptors like the NDA receptor you find the same kind of thing so there are good correlations certainly through experimental manipulation between manipulating the particular molecular mechanisms in the hippocampus finding changes in the physiological signatures of memory long-term potentiation and finding changes in the behavior of the of the animal so you might think these are still these are quite different that you know in the human case declarative memory depends on generating information about facts and so forth the animal you're looking at at spatial memory and in the animal you can't do the you can't do what you can do in humans you can't ask it about facts but you can certainly test spatial memory in humans and people have done that they've done this in a number of different ways maybe one of the more entertaining and one of the initial studies in England was to look at London taxi drivers so it turns out not all of you may know this that if you want to become a taxi driver in London you have to take this test called the knowledge you can look this up on Wikipedia that's supposed to be the hardest test in the world in fact there's lots of websites that will sell you all these CDs and special things on how to become a London how to train for becoming a London taxi driver it it's a sort of extreme training in spatial memory so for those of you that visited London you know sort of Byzantine arrangement of all the different streets and alleys and so forth and you have to have a spatial map of that you have to know where things are located in order to be able to quickly reenact all that spatial layout that you've learned about so that you can very flexibly say I'm at point a what's the shortest route to get to point b so this also illustrates another key aspect of declarative and of declarative memory both verbally and spatially in that it's very flexible so you could use it for many different kinds of things so if you want to get around in a city like London you have to train a lot and you have to bind these things together people have done functional imaging studies in humans the details of these may not be too compelling for you there are more modern ones now but they have looked at this region of the brain the hippocampus in people in London cab drivers and they find that there are indeed both functional and what's shown in this slide here structural changes in the hippocampus and moreover those correlate with how long you've been a taxi driver so you find that there are changes in the hippocampus that correlate with time spent taxi being a taxi driver and people have done similar studies in animals so it seems to be quite a strong again correlation between the hippocampus and spatial memory as there was between the hippocampus and and a verbal declarative memory okay so that's one main summary from this that if you ask people what's declarative memory and you just say well it's your memory for facts and events well memory for facts and events is how you test it in humans but you can't test it that way in animals the idea is that it's a flexible relational form of memory that finds different sensory representations together because of this hierarchical scheme that I sketched for you in the hippocampus and so you could think of this as sort of the point where these pathways that we heard about in vision the what and where processing pathway that went into the parietal and temporal lobes where these come together so you have some item that you're processing there's something about where it's located spatial location here that's processed that funnels into the hippocampus and there's separate information about what it is and this is a little abstract here but these terms here and these different colors stand for particular regions of the medial temporal lobe that get this information so you have these big streams that we had in the visual this is just in the case of vision something analogous is there for other sensory systems would you have this big ventral stream here in the temporal lobe for object identification is more dorsal stream for where things are located in space and these both funnel down into this region and are bound together by the hippocampus last thing just to mention in terms of comparative studies so rodents monkeys humans have been studied a lot but it turns out that birds actually have phenomenal what looks like actually episodic memories as well and people have studied this in corvettes which are birds like crows and jays and scrub jays for instance I will store food and have something that really looks like episodic memory so they're able to remember where they you can watch this if you just go to the foothills here you watch us watch a scrub jay what they will take is you know acorns or any other kind of food that you give them and they were cash these they make caches for the winter so they hide them under pine needles and stuff and they make many caches all over the place lots and lots of caches so they have to remember where those are spatially there's lots of them then they have to remember what they cash and it turns out they can remember what they cash and when they cash that so if you give them perishable food and they cash it they will remember that and they will go to that cash to retrieve the food that is the most perishable before they go to the other caches to cash other foods I remember where they put it what it is and when they put it there and then you can use that flexibly so for instance they also pay attention to other birds to make sure they don't pilfer the caches that they're watching them put the food in so anyway it seems like episodic memory probably evolved independently several times in order for animals to be able to come up with a very flexible way of making use of information like we said at the very beginning of the course of the class making use of multiple sources of information from the past in order to most flexibly guide your behavior into the future so that's the function of declarative memory and we'll stop there and we'll hear about non-declared of memory next Wednesday I have time for a coffee