23/04/2013

Episodic Memory, Hippocampus & Computational Theories Cases like HM highlighted that episodic memory/autobiographical memory was done by the temporal lobe Last week we looked at how the hippocampus is involved in processing spatial information. How is this relevant to episodic/declarative memory. When we talk about episodic memory, we often refer to the work of Endel Tulving; he captured the idea of episodic memory and what it is. In1972 he defined it as binding together information about what happened, where it happened and when it happened. In his thinking he also made the distinction between autonoetic memory (another feature added on to the what where when phenomenon), which referred to the ability of us to undergo mental time travel; a key and important feature, which reflects this recollection, type component of episodic memory. We can recall what we had for breakfast, what we saw on the way to work. I.e. mental time travel Autonoetic consciousness is the human ability to mentally place ourselves in the past, in the future, or in counterfactual situations, and to analyze our own thoughts Wikipedia Semantic memory is the ability to recall facts or knowledge. The distinction is whether you know it or do you just know that it happened. You may know that you were born, but you dont have a memory of it. In the last 5-6 years theres been effort to devise tasks that mimic this episodic/declarative memory in animals. Tulvings response to the question of whether animal can form episodic memory Tulving said evolution is an exceedingly clever tinkerer who can make its creatures perform spectacular feats without necessarily endowing them with sophisticated powers of conscious awareness Animals can never display the same episodic memory that humans show. They cant undergo this spontaneous mental time travel; the conscious awareness of travelling back in time to a particular event. This raises philosophical questions about what consciousness is in humans and non-verbal animals. For some people that absence of a comparative language display means that animals arent at the same conscious levels as humans.

Individuals got round this by asking the question, we know that the hippocampus lights up under conditions where humans are required to remember particular events from a memory task (as well as other regions such as prefrontal cortex). When it comes to knowing something, having a sense of a familiarity that something occurs, there is different neural systems that underpin this process. Hippocampus is possessed not only by rats/mice but also by birds that have a rudimentary hippocampus. Some birds use hippocampus to forms spatial maps of their environment. Birds such as food-storing birds (i.e. store in preparation for winter) store food in thousands of different places and go back to retrieve the food items. Its quite a remarkable feet of memory. The size of the hippocampus tends to vary with the seasons. Birds who store food in this way have a bigger hippocampus.

Experimental Design from Clayton et al. 1998, Cambridge They wanted to find out whether these birds, which display these remarkable memory feats, encode information about what they stored, where they stored it and when they stored it. The three Ws came from Tulving They got birds to store bits of food (peanuts, which theyll eat, or worms, which they prefer Theyd come out of cage and pick up worms/peanuts and put them in dishes in a particular place with a specific background contextual cue (i.e. what and where). The when component was dictated by the length of time between initial storage stage and recovery stages Animals comes in, store peanut in particular location. After 120-hour interval, they would then have another cashing experience where they could store a worm. 4 hours later they had opportunity to retrieve food item. They chose worm

If animals were given worm to store and then 120hour delay and then peanut to store. They were given 4 hour delay and then in recovery stage (the worm was sneakily replace with a decayed worm; so we expect them to choose the peanut) o If you store a worm the day before it will be mouldy. If you store a worm 4 hours ago, it will still be fresh o At the point of which being asked to go look for food, then you think about what you stored more recently. o The most recent thing stored was peanut, but a worm (preferred food) was stored hours ago. If they go to the worm it will be stinky. With that knowledge, the preference will shift to the peanut cache site o The animals have to remember what it stored, when it stored it (4 hours ago or 120 hour ago) and where. o So if animals encoded information about 3 Ws they should show this pattern of selection Next slide shows number of sites that they went to see that either contained nuts or warms at 4hr or 124hr delay. In the group where food reward was allowed to rot, at 4 hour they still showed preference for worms, but this was swapped round when they had to think about where the food reward was located. If animals were trained under similar conditions, except worms not allowed to decay, you can still see the animal show a marred preference for worm location after 4 and 124 hours. If animal can go back to where worms were presented and not decayed then they clearly remember items stored 124 hours ago Pilfer group tried to mimic aspects of things that go on in the wild e.g. bird watching other bids. They trained animals that after certain delay, those locations where theyd be stored had been pilfered. Marked preference for 4 hour delay decreased after 124 hours The birds were trained for a number of days, they acquired knowledge that after 124 hours the worm was nasty. Bar chart a shows that its not due to some forgetting of the worm context, chart b shows that they still know where the worms are This was published in Nature or Science, and the world immediately sat up and was hooked because the birds are integrating information about the Ws. The integrations of the Ws is a core feature of episodic memory o Tulving popped up and said evolution is an exceedingly clever tinkerer o He said potentially it could be based on a simple/associative type of memory system o How can we be told that theyve undergone mental time travel o The problem we face is that autonoetic/conscious recollective process is something that well never get to in animals, its simply too hard and subject to many alternative explanations. o So Clayton called her observations something different. She called this type of memory process episodic-like memory (it was a reaction to the philosophical difficulties associative with animals displaying conscious recollection) o When were studying episodic memory, well refer to this. The evidence of animals binding 3 Ws Dont say that animals show episodic memory, but rather episodic-like memory Many tasked have tried to mimic the procedure; the key problem is that all the tasks take a huge amount of time to train the animals. Whereas in humans its instant.

Recognition Test Recognition memory is very simple; we can test it with sample information (items to look at), then delay and then we give opportunity to identify which item was present This type of memory test has been used in various ways and theres been a number of mathematic models which describe some of the conditions under which performance is affected Recognition performance under these sorts of testing conditions is often characterised by hits (correct responses) or false alarms (misidentify a new item as an old item in the first list) We can work out probability for tests of scoring hits or false alarms Next slide (3 line graphs on it) o We dont need to know details of mathematic models, just the output o wE CAN use models to map out probability of hits/false alarms under different types of testing conditions e.g. when tests are relatively easy/liberal testing conditions and also under conditions where tasks are actually quite hard (conservative) o When you do that and plot the probability of hits and false alarms, you end up with a funny looking curve; a curvilinear relationship between hits and false alarms o These mathematical models are based on real data on real human beings
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o If you look more loosely at this relationship, you also find that in the majority of people this curve becomes asymmetrical; the starts position is above 0. This refers to the presence of some kind of threshold where you can spontaneously recollect items as being part of a list. This asymmetrical curvilinear relationship between hits and false alarms is characteristic of normal human recognition memory (talking about the top line on the top graph). The fact that is tarts about 0 is though to reflect a recollective memory process o Evidence that these curves reflect some real psychological memory mechanisms has been substantiated by testing various patients groups produce ROC curves MCI patients; mild cognitive impairment, mild memory deficits. Most important thing to note is that they do show curvilinear relationship, but these patients, who do not do well on recognition tests, have a marked difference on asymmetrical component of curve. Their ability to use this active recognition process (e.g. ive remember seeing that item because I was scratching my nose when I saw it), this is not present. They cant remember the contextual components of items they were given If you look at Alzheimers patients, there little evidence of any recollective component to memory and really performance is based on familiarity. It doesnt involve where or when information is encoded, contextual features arent there. o Recognition tasks, when given to humans, when mathematic models are applied, we see specific features, which maps onto distinct memory process. The bow shows familiarly memory process, the asymmetrical link shows the recollective memory process. o Some argues that ROC reflect a single trace-strength model; its nothing to do with distinguishing familiarity and recollective element (so there are alternative models) o So I wonder if recognition performance in rats show the same relationships when you plot hits and false alarms against each other Howard Eichenbaum He said I need to design recognition task for rats which allows me to interrogate the same memory characteristics (ROC curves) for rats He did it He designed a task in which rodents dig in pots for a food reward Each pot contained different odour in the sand (e.g. orange, banana, curcumin) and the rats were also required to identify old items (old odours) and new ones. Rats were reinforced for going to new digging material. Recognition = correctly rejecting pots with old odours of digging material in. They altered amount of food available for making a correct response. Motivational aspect was varied systematically They also varied the height of the pot so that the animal had to exert greater effort to get access to food reward; the penalty for making an error was increased By making these changes he effective changed the difficulty of the task (how liberal/conservative they were) He then got rats with hippocampal lesions in task Next slide (with 6 graphs on) a, b and c reminds us of what we see in humans d e and f show us rats in Eichenbaum recognition tests Rats show curvilinear relationship between hits and false alarms as humans; this goes against Tulving When you get hippocampal lesion, you see they only show curvilinear familiarity based aspect, not the asymmetrical staring point which is supposed to reflect the episodic component of being able to recall contextual element of scene. Hippocampal lesions alters ROC curves Rats with hippocampal lesions dont recollect recognition, they only show basic familiarity component which is supported by perirhinal cortex

Next slide Looked at young and aged rats (2 years); the important component is that with ageing (just like in humans0) you see the absence of the asymmetrical curvilinear component

Next slide Robitsek et al 2008 Prefrontal cortex lesions impair recollective recognition memory by increasing the probability of false alarms The hippocampus is talking to their brain systems When you lesion medial prefrontal cortex you disrupt the reflect/recollection component of recognition memory, but leave intact the curvilinear component Many people believe the MPC is adding in the time stamp (when something happens); so if lesion the system providing temporal information then you get a deficit of recollective episode memory int eh brain

Next slide Iordanova et al, 2008, 2009 What-where-when task Rats get placed into conditioning chambers (small boxes decorated with wall paper; some with spots, some with checks) In the morning, the animals goes in spotty box and gets a tone presentation; that is all (no food), just 10 presentations of 10 second tones A minute or so afterwards, animals goes into check box and hears 10 ten-second quicker tone presentations (clicks) Next, spotty box they heart he click (machine gun); then put in check box and animal hears the ton So o Morning session gets spotty box and tone, and checked box and clicks o Afternoon sessions gets other way round It was hoped that animals would learn that theyd go into the spotty box and get a tone and if they were in the check box in the morning theyd get the clicks. It was hoped theyd know that in the afternoon it would be the other way o So what you get and where you get it and when you get it To access animals memory for these events, they then got a couple of session in which the tone was followed by a foot shock The idea behind that is that were revaluing the animals reaction to the auditory cue When a tone is followed by shock, the animals display this by stopping moving a freezing In test, they get exactly the same as in acquisition sessions except theres no auditory cue When animals are placed back in spotty context, it should retried the fact that its the morning and in the spotty context and should get a tone and so it should freeze. When placed in check box at same time of morning, then the check box should retrieve memory of the click (Which was never paired with shock) and should not freeze/be scared the reverse is true for afternoon o Animals is placed in spotty box and animals is fine. But when put in checked box the animal will remember the tone and will freeze Freezing performance is moderated by what they had, where they had it and when they had it Now we need control tasks We wanted to look at simple associations before talking about what where and when. They wanted animals to know a simple association between what and where; so they just had tone spotty morning session and click checks in morning and then revaluation test where tone was paired with shock and so in the text they should freeze more in spotty room o i.e. nothing changes as a function of time of day; its just pairing tone with spotty and click with check o Just what and where, time is not a factor We also evaluated animals ability to evaluate what theyre getting and when o So nature of box must stay consistent o So in morning they get spotty box and ton, in afternoon in spotty box they get click o Morning = tone, afternoon = click o Revalue tone o Animals freeze more in morning (i.e. when tone is presented) and theyre happing in afternoon when clicker is presented o SO just where and when is done Next slide: Hippocampal vs Perirhinal cortex lesions
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Normal animals show a pattern of performance where freezing performance was above 0.5 in morning and below it in afternoon Hippocampal lesion animals dont perform nearly as well Rats with hippocampal lesions cant do this task, nor can rats with perirhinal lesions Rats with perirhinal lesions do okay in what when task, but cant learn auditory cue and where its presented Hippocampal animals can learn simple binary associations of what-where and what when But when asked to combine them in an episodic like manner, they cant do it This was the first compelling demonstration that hippocampal lesions disruption of episodic-like animal task o These are animals will complete cell loss in hippo They wanted to see effect of temporarily stopping hippo from working o They uses GABAergic agonist called Muscimol o When they looked at what where when task the performance was very bad Take home message; lesions disrupt ability to integrate information about what where and when; does not impact ability to form binary association between them Inactivating hippo campus allows animal to show knowledge of simple binary association The Muscimol was just given during the test stage

Is the hippocampus required during condition of the auditory cue? What happens when you put Muscimol in during conditioning (i.e. when getting tone shock pairings) These animals, when hippocampus is shut down during pairing, during test stage, when hippo is working normally again, they cant do it Thats not a performance deficit Simple binary associations were fine Inactivating hippo during paring had an impact on performance for memory of what where and when o Not impact memory for what where o Not impact memory for what when

NMDA-R and Synaptic Plasticity This lead us to think, why would inactivating hippocampus during paring, only affect memory related to integration of these 3 components The tone itself will reactivate memory; retrieve memories of where and when you heard it If youve got eh memory of having a tone in the morning in the spotty box, then when the memory is reflected upon and the animal gets a shock, then the memory of the tone will be present at the animal head at the time it gets shocked Its like being asked to recall the nicest person youve ever met, and then you get hit in the face and this occurs every time you think about this person Therefore next time you see nice person, youd start thinking about this which would lead you to avoid them Because memory reactivation occurs when something bad happened, the memory undergoes a change in value o It becomes nasty o Revaluation process whereby memory undergoes change in how you feel about it o Its like memory being updated i.e. synaptic plasticity changes Memory needs to be re-encoded with different kind of affects Re-encoding involves synaptic plasticity Synaptic plasticity involves NMDA receptors The shock might stop the updating process o So one group had AP5 infused into hippo just before conditioning so that it would be in hippo when animals were retrieving memory o Second group got AP5 infused at the end of session (i.e. after conditioning had occurs) o Third group got AP5 at time of being tested Next slide o Finding ins o Normal animals show standard effect
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o Animals who got AP5 during tone-shock presentation were underperforming o AP5 after revaluation and during test were find Its not the case that having drug on board during paired impaired them They learnt that tone lead to something nasty, but failed to update memory process In another experiment they looked at binary associations o No deficit in performance when looking at simple binary associations o Only when 3 Ws

Is this evidence for episodic-like memory or a more tractable process? In this task theres a time point where episodic-like memory is being updated This updating process relies upon NMDA receptors in hippocampus People try to anthropomorphise these findings; if a task for animals looks like task for humans and call it by a similar name, then other people who are less clever start thinking that the task is a measure of that kind of memory in humans; but animals cant talk to us Rudy and Sutherland 1989 o Configural association theory o You dont need to use the word episodic learning process, but you can use Configural o There are models of learning in animals that speculate that, when you present animals with simultaneous stimuli, this combination of 3 things presented at same time can be encoded by separate neuronal mechanism; a configural unit o This other neuron is encoding the fact that these 2 or 3 things are happening at the same time and it fires when these things are happening together o The presentation of all3 elements is encoded by a single neuron which connects with another neuron that encodes that food is presented; o Episodic means something different for animals, we should use configural for animals

How does information processing by the hippocampus encode and retrieve memory? Pattern completion and pattern separation, Mar 1971 Computational theories of hippocampal function o The theories have features in common o They refer to processes such as patter completion and pattern separation o These 2 terms refer to the fact that there are processes within hippocampus which allow you to take information coming into hippocampus (e.g. information represented by 1000 inputs) and recode it as just 2 neurons firing. o So you get 1000inputs coming in, representing an event, the hippocampus has a mechanism for representing the event more simply such as just 2 neurons which encode the event Orthogonalisation Hippo must be able to represent complex event with simpler neuronal code Reason for this; episodic memories consist of 100s of different events but have something in common I.e. us, our cat or our parents or a bike etc. Elements of memories are common, But we can separate them in memory space even though they have similar items in common IF we couldnt separate events out then our memories would get confused We can do this by having the rich information that comes in, with all elements represent by 1 neuron When another event involving features in common and unique feature, you can separate the memory out. The other event with overlapping features can nevertheless be encoded by a separate neuron o This is pattern separation o This is important because other memories with something in common oudl become confused o Pattern completion: sometimes there are cues that are presented in our environment which make us think about things
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So 3-pronged gardening fork might make us think about event we were told about (eg. In his brothers head) In any occasion, we would think much of it The gardening fork would make us think of event; one pattern comes into brain and revokes memory Pattern has been completed By giving neuronal system one piece of puzzle the rest of it comes in Computational models say hippo does both of these things o But you cant have same architecture doing pattern completion and pattern separation o But you can separate out processes anatomically in hippocampus o Hippo gets input from ERhC and goes on to DG and then CA1 o The DG gets input from Perforant path and sends information onto CA3 region (mossy fibres) o CA3 pyramidal cells then projects onto CA1 cells (Schaffer collateral) o The DG performs does pattern separation o The CA3 area does pattern completion Next slide, 4 squares o If you take inputs from grid cells in ERhC and look at way DG encodes information we see that patterns in ERhC are encoded by 1 DJ cell o A different pattern in ERhC cell is represented by one other cell in DG gyrus o Because of complex inhibitory signal in the DG, the signal form the ERhC is encoded by one cell The CA3 region = pattern completion o They believe this because the CA3 region as pyramidal cells in which you get projects from the same pyramidal cells which comes back into dendrites of other pyramidal cells o Its has characteristics of an auto-associative network o If you have input from ERhC onto CA3 region, it elicits activity of synaptic areas in CA3 region (plastic changes) o If you have partial input, i.e. 1 input neuron that represents a gardening fork, and follow it round, it elicits activity in 2 nodes o By activating these nodes, other 2 nodes are activated too, so pattern is complete o Even though youve only got one input o These collaterals which feed back onto themselves are responsible for pattern emerging o The CA3 network is a system that will happily do pattern completion because of its architecture The CA1 region acts as an output to the cortex; also acts as a mismatch detector; comparing Shaffer collateral output with direct input from the entorhinal cortex