Learning, Memory and Amnesia

Radial arm maze test 2

Ability to refrain from visiting an arm more than once a day- working memory- temporary memory that's necessary for successful performance on a task on which working Rats with hippocampal lesions display major deficits in both reference memory and working memory measures of radial arm maze performance

Concept cells more

Accordingly, it has been suggested that images trigger activity in circuits of concept cells in the medial temporal lobes- Quiroga 2012 Although it is not yet clear how Jennifer Aniston neurons contribute to the storage of memories, it is clear that they play a role, and their discovery is a major step forward

Induction of LTP- learning 5

Accordingly, the requirement for co-occurrence and the dependence of NMDA receptors on simultaneous binding and partial depolarization mean that, under natural conditions, synaptic facilitation records the fact that there has been simultaneous activity in at least two converging inputs to the postsynaptic neuron— as would be produced, for example, by the "simultaneous" presentation of a conditional stimulus and an unconditional stimulus.

Incomplete pictures test 2

Asked identify 20 objects from set one- most fragmented Unrecognised presented in set 2 version and so on until all identified HM improved performance 1 hour later- Milner et al 1968 Couldn't recall previously performing task

Synaptic mechanisms of learning and memory- long term potentiation

Because Hebb's hypothesis that enduring facilitations of synaptic transmission are the neural bases of learning and memory was so influential, there was great excitement when such an effect was discovered. 1973- Bliss and Lømø showed that there is a facilitation of synaptic transmission following high-frequency electrical stimulation applied to presynaptic neurons. This phenomenon has been termed long-term potentiation (Ltp) . LTP has been demonstrated in many species and in many parts of their brains, but it has been most frequently studied in the rodent hippocampus.

Hard to spot

Difficult to spot episodic memory deficits even when extreme In part coz neuropsychologists usually no way of knowing true events of ps life Also coz ps become efficient at providing semantic answers to episodic qs

Contributions of HM 2

Discovery bilateral medial temporal lobectomy abolished HMs ability to form certain kinds of LTM without disrupting performance in STM tests and remote memory supporter theory tart different storage for STM, LTM and remote memory HMs specific problems appeared to be a difficulty in memory consolidation- translation if STM into LTM

Incomplete pictures test

Discovery capable of forming LTM for mirror drawing suggested sensorimotor tasks were one exception to inability to form LTM View challenged by demonstration that HM could also form new LTM for incomplete pictures task- Gollin 1960 A non sensorimotor test that employ 5 sets of fragmented drawings Each set contains drawings of same 20 objects but sets differ in degree of completeness

Bilateral medial temporal lobectomy 2

Generalised seizures all but eliminated, partial seizures reduced lots Level anticonvulsant medication reduced IQ increased from 104-118 Last p to revive operation due to devastating amnesiac effects Retrograde/anterograde amnesia

Grid cells 2

The even spacing of the place fields in the grid cells could enable spatial computations in hippocampal place cells. Grid cells have also been identified in other species including human patients- Jacobs et al 2013 Other types of neurons in the entorhinal cortex are associated with spatial location: For example, head - direction cells are tuned to the direction of head orientation, and border cells fire when the subject is near the borders of its immediate environment- Rowland & Moser 2015

Variability of LTP 2

There is also metaplasticity , which refers to the fact that LTP and/or LTD induction can be modulated by prior synaptic activity (see Hulme, Jones, & Abraham, 2013) Presumably, a full understanding of LTP and its role in memory will require an understanding of LTD and metaplasticity. And we still don't know what role glial cells play in LTP (see Jones, 2015)

Conclusions

These findings have led to two major conclusions: (1) Memories are stored diffusely in the brain and thus can survive destruction of any single structure; and (2) memories become more resistant to disruption over time.

Additional support 2

(4) many drugs that influence learning and memory have parallel effects on LTP; (5) the induction of maximal LTP blocks the learning of a Morris water maze until the LTP has subsided; (6) mutant mice that display little hippocampal LTP have difficulty learning the Morris water maze; (7) behavioral changes that appear to be memories can be induced in mice via LTP (Nabavi et al., 2014); and (8) LTP occurs at specific synapses that have been shown to participate in learning and memory in simple nervous systems.

Infantile amnesia experiment 1

(Newcombe & Fox, 1994), children were shown a series of photographs of preschool-aged children, some of whom had been their preschool classmates. The children recognized a few of their former preschool classmates. However, whether they explicitly remembered a former classmate or not, they consistently displayed a large skin conductance response to the photographs of their former classmates but not to the control photographs.

The induction of NMDA-receptor- mediated LTP.

1 If the postsynaptic neuron is not depolarized when glutamate binds its receptors, the NMDA receptors permit the influx of only a few calcium and no LTP is produced. 2 the postsynaptic neuron is depolarized when glutamate binds to its receptors, the NMDA permit the entry of many calcium ions, which induce LTP.

Long-term potentiation in the granule cell layer of the rat hippocampal dentate gyrus.

A single pulse of stimulation was administered to the perforant path, and the baseline response was recorded by an extracellular electrode in the granule cell layer. Then, several trains of intense high-frequency stimulation were applied to the perforant path to induce the LTP. A single pulse of stimulation was administered 1 day later and again 1 week later to assess the magnitude of and duration of the potentiation. One measure of LTP is the increased amplitude of the population spike , in this case, the spike created by the firing of a greater number of granule cells.

Learning and memory

2 ways of thinking about same thing Both neuronplastic processes, deal with ability of brain to change functioning in response to experience Learning deals with how experience changes the brain Memory deals with how these changes are stored and reactivated Without ability to learn and remember, would experience every moment as if waking from life long sleep Everyone stranger etc

Additional support

Additional support for the idea that LTP is related to the neural mechanisms of learning and memCell ory has come from several observations (1) LTP can be elicited by low levels of stimulation that mimic normal neural activity; (2) LTP effects are most prominent in struc3 tures that have been implicated in learning and memory, such as the hippocampus; (3) learning can produce LTP-like changes in the hippocampus;

HM long term memory

Almost total inability to form new LTM Once stopped thinking about experience, lost forever Couldnt remember new addresss, people met after surgery, read same things without recognising them 5 tests used to assess LTM, changed way think about brain and memory

Neurons of medial temporal lobes and memory

Although first suggestion that medial temporal lobes play major role in memory came from study of effects of damage to that area, study of neurons also enlightening In rats found bilateral lesions of hippocampus invariably disrupt performance of tasks that involve memory for spatial locations Disrupt performance on Morris water maze test and radial arm maze test

Controversial 2

Although most obvious damage following cerebral ischemia is in CA1 subfield of hippocampus there's substantial damage to other areas that's more diffuse and more difficult to quantify- Groen et al 2005 Allen et al 2006- ischemic ps with greatly reduced hippocampal volume much more likely for suffer from anterograde amnesia however same ps also tended to have extensive neocortical damage

Smart drugs 3

Although nootropics are often marketed to healthy adults, most research has been done on either nonhumans or humans with memory difficulties (i.e., the elderly). The relevant research with humans tends to be of low quality, with few participants and poor controls. For each purported nootropic, there are typically a few positive findings on which the vendors focus; however, these findings are often difficult to replicate or represent very small effect sizes (see Farah, 2015).

Comparative studies of hippocampus and spatial memory 2

Although research on a variety of species indicates that the hippocampus does play a role in spatial memory, the effects of hippocampal damage on the performance of spatial memory tasks in humans and other primates have been less consistent- Henke et al 1999 May be that spatial memory in humans and monkeys is often tested while they remain stationary and make judgments of locations on computer screens, whereas spatial memory in rats, mice, and birds is typically studied as they navigate through test environments- Aghajan et al 2015

Transient global amnesia 2

Amnesia is transient, typically lasting only 4-6 hours Sudden onset suggested caused by stroke however until recently no brain pathology could be linked to disorder Identified abnormalities to CA1 subfield of hippocampus- Arena and Rabinstein 2015 Time course if abnormalities- usually apparent for several hours after beginning of attack and usually cleared up 10 days later suggestive of stroke induced damage- Hunter 2011

RB 2

Amnesia not as severe as HM but comparable Brain damage restricted largely to pyramidal cell layer of just one part of hippocampus- CA1 subfield Hippocampus contains- CA1-4 subfields and dentate gyrus CA- cornu ammonis, another name for hippocampus

Amygdala

Amygdala- thought to play a special role in memory for the emotional significance of experiences (see Herry & Johansen, 2014. Rats with amygdalar lesions, unlike intact rats, do not respond with fear to a neutral stimulus that has previously been followed by electric foot shock (see Maren, 2015) Bechara et al (1995) reported the case of a patient with bilateral damage to the amygdala who could not acquire conditioned autonomic startle responses to various visual or auditory stimuli but had good explicit memory for the training.

Induction of LTP- learning 2

An important characteristic of the induction of LTP at glutamin1 ergic synapses stems from the nainduction ture of the NMDA receptor and the requirement for co-occurrence of firing for LTP to occur. This characteristic is not obvious under the usual, but unnatural, experimental condition in which LTP is induced by high-intensity, high-frequency stimulation, which always activates the postsynaptic neurons through massive temporal and spatial summation. However, when a more natural, low-intensity stimulation is applied, the postsynaptic neurons do not fire, and thus LTP is not induced— unless the postsynaptic neurons are already partially depolarized so that their calcium channels open wide when glutamate binds to their NMDA receptors.

Neuroanatomical basis of object recognition deficits resulting from bilateral medial temporal lobe lobectomy 2

Bilateral surgical removal of hippocampus produces only modest deficits and bilateral destruction of amygdala produces none Reports object recognition memory severely disrupted by medial temporal cortex lesions but only moderately by hippocampal lesions led to resurgence of interest in case of RB Left amnesic following ischemic accident that occurred during heart surgery and subsequent analysis of brain revealed cell loss restricted largely to pyramidal cell layer of CA1 hippocampal subfield

Amnesia after concussion

Blows to head that don't penetrate skull but are severe enough to produce concussion are most common cause of amnesia Amnesia following a non penetrating blow to head called posttraumatic amnesia PTA

Inferotemporal cortex 2

Bussey and Saksida (2005) have argued that the inferior temporal cortex, in concert with adjacent perirhinal cortex (see Suzuki & Naya, 2014), plays an important role in storing memories of visual input. In support of this view, Naya, Yoshida, and Miyashita (2001) recorded the responses of neurons in inferotemporal cortex and perirhinal cortex while monkeys learned the relation between the two items in pairs of visual images

Contributions of HM 1

By showing medial temporal lobes play important role in memory, HMs case challenged view memory functions diffusely distributed throughout brain Renewed his flirts to relate individual brain structure to specific mnemonic processed Caused massive research effort aimed at clarifying mnemonic functions of hippocampus and other medial temporal lobe structures

Cerebellum and striatum

Cerebellum and striatum-. Just as explicit memoprefrontal ries of experiences are presumed to be stored in the circuits of the brain that mediated their original perception, implicit memories of sensorimotor learning are presumed to be stored in sensorimotor circuits (see Graybiel & Grafton, 2015). Most research on the neural mechanisms of memory for sensorimotor tasks has focused on two structures: the cerebellum and the striatum.

Posttraumatic amnesia

Coma following severe blow to heed usually lasts a few seconds or minutes but in severe cases can last weeks Once conscious, experiences period of confusion Typically not tested by neuropsychologist until after confusion Testing usually reveals permanent retrograde amnesia for events leading up to blow and permanent anterograde a,media for many of events that occurred during period of confusion

Amnesia of Korsakoff's syndrome

Common in people who have consumed large amounts of alcohol Largely attributable to brain damage associated with thiamine deficiency that often accompanies heavy alcohol consumption Advanced stages- characterised by variety of motor and sensory problems eg extreme confusion, personality changes, risk of death from liver or heart disorders Post mortems typically reveal lesions to medial diencephalon- medial thalamus and medial hypothalamus and diffuse damage to several other structures eg neocortex, hippocampus and cerebellum

3 part process

Conceiving of LTP as a three-part process, many researchers are investigating the mechanisms of inducas tion, maintenance , and expression —that is, the processes by which high-frequency stimulations induce LTP (learntime— ing), the changes responsible for the maintenance of LTP (memory), and the changes that allow it to be expressed during the test (recall).

Hippocampal place cells and entorhinal grid cells

Consistent with view that hippocampus plays role in spatial processing is fact that many hippocampal neurons are place cells- Moser and Moser 2016 Neurons that respond on,h when subject is in specific locations When rate placed in unfamiliar test environment, none of its hippocampal neurons have a place field in that environment then as familiarises itself, many hippocampal neurons acquire a place field in it, each fires only when rat is in particular part of test environment

Delayed non matching to sample test 3

Development of delayed non matching to sample test for monkeys provided a means of testing the assumption that the amnesia resulting from medial temporal lobe damage is entirely consequence of hippocampal damage 3 major temporal lobe structures- hippocampus, amygdala and adjacent medial temporal cortex

Posttraumatic amnesia 2

Duration of period of confusion and anterograde amnesia typically longer than that of coma which typically longer than period of retrograde amnesia More severe blows tend to produce longer comas, longer periods of confusion and longer periods of amnesia Islands of memory- surviving memories for isolated events that occurred during periods for which other memories been wiped out

Study 2

ECS disrupted retention of TV shows that had played in 3 years prior to treatment but not those that played earlier Current view of memory consolidation is that it continues for very long time if not indefinitely- Dudai and Morris 2013 Evidence indicates lasting memories become more and more resistant to disruption throughout life Each time memory activated, it's updated and linked to additional memories- Sandrini, Cohen and Censor 2015 Additional links increase memory's resistance to disruption by cerebral trauma such as concussion or ECS

Hippocampal place cells and entorhinal grid cells 2

Each place cell has place field in different part of environment Place cells have been identified in variety of species including humans- Miller et al 2013 By placing rat in ambiguous situation in familiar test environment, possible to determine where rat thinks it is from route it takes to get to location in environment where previously rewarded Kubie et al 2007- firing of rats place cells indicates where rat thinks it is in test environment not necessarily where actually is

Implicit/explicit

Even though no explicit memory of seeing original list Discovery two memory systems- implicit and explicit asked q of why Presumably implicit first evolve as more simple as doesn't involve consciousness Experiment with amnesic ps- Reber, Knowlton and Squire 1996 and amnesic monkeys with medial temporal lobe lesions- Buckley and Gaffan 1998 suggest answer is flexibility

Synaptic mechanisms of learning and memory- long term potentiation 2

Figure 11.19 illustrates LTP in the granule cell layer of the rat hippocampal dentate gyrus. First, a single lowintensity pulse of current was delivered to the perforant path (the major input to the dentate gyrus), and the response was recorded through an extracellular multipleunit electrode in the granule cell layer of the hippocampal dentate gyrus; the purpose of this initial stimulation was to determine the initial response baseline.

Mirror drawing test

First indication HMs anterograde amnesia didn't involve all LTM Milner 1965- draw line within boundaries if star shaped target by watching hand in mirror Asked to trace star 10 times on each of 3 consecutive days and recorded no of times went outside boundary Performance improved over 3 days which indicates retention of task despite improved performance couldn't recall ever doing task before

Animal model failure

First reports of HMs case in 1950s triggered massive effort to develop an animal model of his disorder so could be subjected to experimental analysis In early years dismal failure, lesions of medial temporal lobe structures didn't produce severe anterograde amnesia in rats, monkeys or other nonhuman species

Amnesia of Alzheimer's disease

First sign of Alzheimer's disease us often mild deterioration of memory Disorder is progressive, eventually dementia develops and becomes so severe that p incapable of simple activities eg eating Terminal Efforts to understand neural basis of Alzheimer's amnesia focused on predementia Alzheimer's ps Memory deficits more general than others

Contributions of HM 3

First to reveal amnesia p night claim no recollection of previous experience while demonstrating memory for it by improved performance Led to creation of two distinct catagories of LTM Conscious LTM- explicit memories/declarative memories LTM demonstrated by improved test performance without conscious awareness- implicit memories/non declarative memories

Experiment 2 2

Following this test of implicit memory, explicit memory was assessed by asking the participants which of the drawings they remembered seeing before. The 5-year-olds and adults showed better explicit memory than the 3-year-olds did; that is, they were more likely to recall seeing drawings from the original series. However, all three groups displayed substantial implicit memory: All participants were able to identify the drawings they had previously seen sooner, even when they had no conscious recollection of them.

Comparative studies of hippocampus and spatial memory

Food-caching birds must have remarkable spatial memories because, in order to survive, they must remember the locations of hundreds of food caches scattered around their territories. In one study, Sherry and Vaccarino (1989) found that food-caching species tended to have larger hippocampuses than related nonfood-caching species

Cerebellum and striatum 3

For example, Knowlton, Mangels, and Squire (1996) found that the Parkinson's patients, who had striatal damage, could not solve a probabilistic discrimination problem. The problem was a computer "weather forecasting" game, and the task was to correctly predict the weather by pressing one of two keys, rain or shine. The patients based their predictions on stimulus cards presented on the screen— each card had a different probability of leading to sunshine, which the patients had to learn and remember. The Parkinson's patients did not improve over 50 trials, although they displayed normal explicit (conscious) memory for the training episodes. In contrast, amnesic patients with medial temporal lobe or medial diencephalic damage displayed marked improvement in performance but had no explicit memory of their training.

Gradients of retrograde amnesia and memory consolidation

Gradients of retrograde amnesia after concussion seem to provide evidence for memory consolidstion The fact that concussions preferentially disrupt recent memories suggests that the storage of older memories has been strengthened ie consolidated Classic theory of memory consolidations is Hebb's theory Argues memories of experiences stored in short term by neural activity reverberating/circulating in closed circuits

Complicate

Gradually insidious onset and progressive development complicate study of resulting retrograde amnesia Never clear to what extent Korkasoff amnesia for recent events reflects retrograde disruption of existing memories or gradually increasing anterograde blockage of formation of new memories

Grid cells

Grid cells are entorhinal neurons that each have an extensive array of evenly spaced place fields, producing a pattern reminiscent of graph paper- Moser & Moser 2013 The distance between the evenly spaced place fields is flexible; in experimental animals kept in smaller or oddly shaped environments, the fields are closer together or sheared, respectively- Krupic et al 2015

Bilateral medial temporal lobectomy

HM contributed more than any one to understanding of neuropsychology of memory 1953- medial portions of temporal lobes removed to treat severe epilepsy Removal of one medial temporal love proved effective for so with unilateral temporal lobe focus, decision made to remove both including most of hippocampus, amygdala and adjacent cortex Lobectomy- lobe or major part removed Lobotomy- lobe or major part seperated by cut but not removed

Block tapping memory span test

HM had global amnesia- for info presented in all senses Milner 1971- demonstrated HMs amnesia not restricted to verbal material 9 blocks spread out, asked to watch touch sequence of them and repeat sequence HM had a block tapping span of 5 blocks, in normal range but couldn't learn to correctly touch sequence of 6 blocks even when same sequence repeated 12 times

Pavlovian conditioning

HM learned eye blink Pavlovian conditioning task but at slow rate- Woodruff-Pak 1993 Tone sounded just before puff of air blown in eye Trials repeated until tone alone elicited eye blink Two years later retained conditioned response almost perfectly although no conscious recollection of training

Hippocampus and consolidation

HM provided evidence of memory consolidation and seemed to suggest that hippocampus played special role in it To account for fact that bilateral medial temporal lobectomy disrupted only those retrograde memories acquired in the few years before HMs surgery, Scoville and Milner 1957 suggested memories temporarily stored in hippocampus until can be transferred into more stable cortical storage system Theory known as standard consolidstion theory or dual trace theory

Semantic and episodic memories

HM was able to form very few new explicit memories however most ppl with medial temporal lobe amnesia display memory deficits that are less complete Study of these amnesics found explicit memories two catagories and tend to have greater difficulty with episodic memories Semantic- general facts or information Episodic- particular events of ones life Two types- Squire et al 2015

Induction of LTP- learning 4

However, if the postsynaptic neuron were partially depolarized by input from other neurons when the presynaptic neuron fired, the binding of the glutamate NMDA to the NMDA receptors would receptor open wide the calcium channels, calcium ions would flow into the postsynaptic neuron, spine and transmission across the synapses between the presynaptic and postsynaptic neuron would be potentiated.

Amygdala 2

However, there is little evidence that the amygdala stores memories; it appears to be involved in strengthening emotionally significant memories stored in other structures (Do-Monte, Quiñones-Laracuente, & Quirk, 2015. The amygdala might be the reason why emotion-provoking events are remembered better than neutral events (see Dunsmoor et al., 2015)

Anterograde amnesia

If found to have this, next step to determine whether difficulty in storing new memories influences short term memory, long term memory or both HM mild retrograde amnesia for events that occurred in two years before surgery, more remote events normal Short term anterograde memory remained normal Eg his digit span was 6 digits- Wickelgren 1967

Experiment 2

In a second study of infantile amnesia, Drummey and Newcombe (1995) used a version of the incomplete-pictures test. First, they showed a series of drawings to 3-year-olds, 5-year-olds, and adults. Three months later, the researchers assessed the implicit memories for these drawings by asking each participant to identify them ("It's a car," "It's a chair," etc.) and some control drawings as quickly as they could. During the test, the drawings were first presented badly out of focus, but became progressively sharper over time.

Amnesia of Alzheimer's disease 2

In addition to major anterograde and retrograde deficits in tests of explicit memory, often display deficits in STM and in some implicit memory Implicit memory for verbal and perceptual material often deficient but implicit memory for sensorimotor learning isn't- Postle, Corkin and Growden 1996 Level of acetylcholine greatly reduced in brains of Alzheimer's ps

Implicit/explicit 2

In both experiments, amnesic subjects learned implicit learning task as well as control subjects did However if asked to use implicit knowledge in different way or different context they failed Presumably evolution of exploit memory system provided for flexible use of information

Neuroanatomical basis of object recognition deficits resulting from bilateral medial temporal lobe lobectomy

In early 1990s, researchers began assessing relative effects of lesions to various medial temporal lobe structured on performance in delayed non matching to sample test in monkeys and rats Challenges to view hippocampal damage is critical factor in medial temporal lobe amnesia quickly accumulated Bilateral surgical removal of medial temporal cortex consistently produces severe and permanent deficits in performance on delayed non matching to sample test

Engram cells depression

In essence, researchers are now able to observe, suppress, or activate engram cells in different parts of the nervous system. For example, researchers have been able to reverse depressive-like behavior in mice by optogenetically reactivating hippocampal dentate granule cells that had previously been active during the encoding of a positive experience (Ramirez et al., 2015).

Animal models of object recognition amnesia, the delayed non matching to sample test

In mid 1970s, animal model of his disorder developed Major breakthrough coz opened uo neuroanatomy of medial temporal lobe amnesia to experimental investigation Gaffan 1974 and Mishkin and Delacour 1975- showed monkeys with bilateral medial temporal lobectomies major problems forming LTM for objects encountered in delayed non matching to sample test

Replicated

In monkeys- Zola-Morgan et al 1992 In rats- Wood et al 1993 In both monkeys and rats, global cerebral ischemic leads to a loss of CA1 hippocampal pyramidal cells and severe deficits in performance on delayed non matching to sample test

Engram cells

In optogenetics, neuroscientists insert an opsin gene into particular neurons, after which they can then use light to either hyperpolarize or depolarize those neurons In recent years, this tool has been used extensively in studies of learning and memory in mice (see Goshen, 2014). One line of research has been particularly interesting because it can shed light on the location of the neurons that maintain an engram ( engram cells )—see Josselyn, Köhler, and Frankland (2015).

Reconsolidation 2

Infusion produced retrograde amnesia for fear conditioning even though original conditioning trial occurre many days before Most research on reconsolidation involved fear conditioning, but some evidence suggests that it may be a general phenomenon in nervous system- Bonin and De Koninck 2015

Perspective of hippocampus changes

Initially thought site of temporary storage for newly formed memories Soon discovered structures of medial temporal lobes have a more specific function, appear to play role only in explicit episodic memories Then discovered role of hippo malus in object recognition memory minor compared to adjacent medial temporal cortex Now considered one of several brain structures that play important roles in memory

Morris water maze test

Intact rats placed at various locations in a circular pool of murky water rapidly learn to swim to a stationary platform hidden just below the surface Rats with hippocampal lesions learn this simple task with great difficulty

Maintenance and Expression of LTP: Storage and Recall 3

It became apparent that maintenance of LTP involves structural changes, which depend on protein synthesis. The discovery that LTP causes structural changes was exciting because the structure of neurons and neural circuits had been assumed to be static. Many kinds of structural changes have been described (e.g., increases in number and size of synapses, increases in number and size of postsynaptic dendritic spines, changes in presynaptic and postsynaptic membranes, and changes in dendritic branching), and the changes have turned out to occur far more rapidly and more frequently than was once assumed (see Bliss & Collingridge, 2013)

Concept cells 3

Jennifer Aniston neurons are highly selective. Each neuron responded to only a small number of test objects or individuals— often only one could be found. Their responses are highly invariant, If a neuron responded to a particular object on test 1, it tended to respond to that object on all subsequent tests. Jennifer Aniston cells of the hippocampus were more selective and more invariant than those of the other medial temporal lobe structures (i.e., parahippocampal cortex, perirhinal cortex, entorhinal cortex, and amygdala).

LTP

LTP is among the most widely studied neuroscieninvertebrate tific phenomena. Why? The reason goes back to 1949 and Hebb's influential theory of memory. The synaptic changes that Hebb hypothesized as underlying long-term memory to be the same kind of changes that underlie LTP (see Lisman, Grace, & Duzel, 2011). LTP has two key properties that Hebb proposed characteristics of the physiological mechanisms of learning and memory. First, LTP can last for a long for several months after multiple high-frequency stimulations (see Abraham, 2006).

Where are memories stored?

Lashley and many who subsequently took up the search used the lesion method. If a particular structure were the storage site for all memories of a particular type, then destruction of that structure should eliminate all memories of that type that were acquired prior to the lesion. No brain structure has shown this result: Lesions of particular structures tend to produce either no retrograde amnesia at all or retrograde amnesia for only the experiences that occurred in the days or weeks just before the surgery.

Gradients of retrograde amnesia and memory consolidation 3

Length of period of retrograde amnesia produced by ECS would provide an estimate of amount of time needed for memory consolidation Many studies used ECS to study duration of consolidation, humans and animals Hebb's theory implies memory consolidation relatively brief, few seconds or minutes, about as long as specific patterns of reverberatory neural activity could be maintained Many studies found evidence for much longer gradients

Contradiction

Little support to standard consolidation theory Temporally graded retrograde amnesia is a feature of many forms of amnesia, so seems unlikely hippocampus plays special role in consolidation Appears when a conscious experience occurs, rapidly and sparsely encoded in a distributed fashion throughout hippocampus and other involved structures

KC more

Memory problems far less obvious that would expect Does well using semantic memory No difficulty having conversation Cannot time travel, can't imagine his future any better than recall his past

Delayed non matching to sample test

Monkey presented with distinctive object- sample object, under which finds food After delay, monkey presented with two test objects- sample object and unfamiliar object Monkey must remember sample object so that it can select unfamiliar object to obtain food concealed beneath it Intact well trained monkeys performed correctly about 90% trials when retention intervals were few minutes or less

Delayed non matching to sample test 2

Monkeys with bilateral medial temporal lobe lesions had major object recognition deficits Modelled those of HM Eg Monkeys performance normal at delays of few seconds but fell off to near chance levels at delays of several minutes Performance extremely susceptible to disruptive effects of distraction- Squire and Zola-Morgan 1985 Humans with medial temporal lobe amnesia tested in delayed non matching to sample test and performance mirrored monkeys

Alzheimers disease

Moreover, researchers have shown that in transgenic mouse models of Alzheimer's disease, activating engram cells leads to the retrieval of memories that are otherwise inaccessible— suggesting that the memory deficits of Alzheimer's disease are retrieval deficits rather than encoding deficits- Roy et al., 2016

Variability of LTP

Most of the research on LTP has focused on NMDAreceptor- mediated LTP in the hippocampus. It is now clear that NMDA-receptor- mediated LTP involves a complex array of changes that are difficult to sort out. In addition, LTP has been documented in many other parts of the CNS, where it tends to be mediated by different mechanisms (see Grau, 2014; Gruart et al., 2015). There is also LTD ( long-term depression ), which is the flip side of LTP and occurs in response to prolonged low-frequency stimulation of presynaptic neurons (see Atwood, Lovinger, & Mathur, 2014)

Case study

NA Medial diencephalic amnesia Teuber, Milner and Vaughan 1968 Stabbed up nostril, went through brain When tested 3 years later, retrograde amnesia decreased in duration covering only events that occurred in two weeks before accident Recall of day to day events that occurred after the accident has been extremely poor

Contradiction 2

Nadel and Moscovitch- retained memories become progressively more resistant to disruption by hippocampal damage coz each time similar experience occurs or original memory recalled, a new engram- a change in brain that stored a memory, is established and linked to original engram Makes memory easier to recall and original engram more difficult to disrupt

Medial temporal lobe amnesia

Neuropsychological ps with a profile of mnemonic deficits similar to HM, with preserved intellectual functioning and evidence of medial temporal lobe damage said to suffer from medial temporal lobe amnesia Research shown HMs difficulty in forming explicit LTM while retaining ability to form implicit LTM not unique to him Symptom of medial temporal lobe amnesia as well as many other amnesic disorders Assessment of implicit LTM important role in study of memory- Reber 2013

Smart drugs

Nootropics , or smart drugs , are substances (drugs, supplements, herbal extracts, etc.) that are thought to improve memory. The shelves of health food stores are full of them, and even more are available on the Internet. Ginkgo biloba extracts, ginseng extracts, multivitamins, glucose, cholinergic agonists, Piracetam, antioxidants, phospholipids, stimulants (e.g., amphetamine, methylphenidate), and many more. Those offering nootropics for sale claim that scientific evidence has proven that these substances improve the memories of healthy children and adults and block the adverse effects of aging on memory.

Why failure

Not initially apparent HMs anterograde amnesia didn't extend to all kinds of LTM, that is it was specific to explicit LTM and most animal memory tests widely used in 1950s and 1960s tests of implicit memory Incorrectly assumed amnesic effects of medial temporal lobe lesions were largely if not entirely attributable to hippocampus damage and most efforts to develop animal models of medial temporal lobe amnesia thus focused on hippocampal lesions

Inferotemporal cortex

Numerous electrophysiological recording and functional brain-imaging studies of memory have led to the same important conclusion: Areas of the brain that are active during the retention of an experience tend to be the same ones active during the original experience. This has focused attention on the mnemonic functions of the sensory and motor areas of the brain. In particular, attention has focused on inferotemporal cortex (cortex of the inferior temporal cortex), which has complex visual functions— see Lehky and Tanaka (2016)

Maintenance and Expression of LTP: Storage and Recall 2

Once it became apparent that LTP occurs only at specific synapses on a postsynaptic neuron, it was clear that there must be a mechanism for keeping the events at one set of synapses on a postsynaptic neuron from affecting other synapses on the same neuron. This specificity is due to the dendritic spines ; the calcium ions that enter a dendritic spine do not readily pass out of it, and thus they exert their effects locally (see Attardo, Fitzgerald, & Schnitzer, 2015;

Entorhinal cortex

One line of research on hippocampal place cells focused on entorhinal cortex- an area of the medial temporal cortex that is a major source of neural signals to the hippocampus A possible answer to the question of how hippocampal place cells obtain their spatial information came from the discovery of so-called grid cells in the entorhinal cortex.

Reconsolodation

One theoretical construct that recently attracted research attention- Bonin and De Koninck 2015 Hypothesis is that each time a memory is retrieved from long term storage, it is temporarily held in labile- changeable or unstable STM where susceptible to posttraumatic amnesia until it's reconsolidated Nader, Schafe and LeDoux 2000- infused the protein synthesis inhibitor anisomycin into amygdala of rats shortcut after rats required to recall a fear conditioning trial

Prefrontal cortex 2

Patients with large prefrontal lesions often display both anterograde and retrograde deficits in memory for the temporal order of events, even when they can remember the events themselves. They also display deficits in working memory (the ability to maintain relevant memories while a task is being completed)—see D'Esposito and Postle (2015) As a result of these two deficits, patients with prefrontal cortex damage often have difficulty performing tasks that involve a series of responses (see Colvin et al 2001)

Case study

Penfield & Evans, 1935- Before her brain damage, she had been an excellent cook; and afterward, she still remembered her favorite recipes and how to perform each individual cooking technique. However, she was incapable of preparing even simple meals because she could not carry out the various steps in proper sequence.

Semantic and episodic memories 2

People with medial temporal lobe amnesia have difficulty with episodic memories Tulving 2002- major force in research of semantic episodic dichotomy KC- suffered brain damage including medial temporal lobes, other cognitive abilities normal Severe amnesia for personal experiences Covers entire life

Prefrontal cortex

Prefrontal cortex- ps with damage to the cortex (the area of frontal cortex anterior to motor cortex) are not grossly amnesic, they often display no deficits at all on conventional tests of memory. This lack of reliable memory deficits in ps with prefrontal damage may in part result from the fact that different parts of the prefrontal cortex play different roles in memory, and that patients with damage to different areas of prefrontal cortex are often combined for analysis.

Effects of global cerebral ischemia on the hippocampus and memory

Ps who have experienced global cerebral ischemia- interruption of bloody supply to entire brains, often suffer from medial temporal lobe amnesia RB- Zola-Morgan, Squire and Amaral 1986 Had cardiac bypass surgery, pump circulating RBs blood broke down Resulting ischemic brain damage left amnesic

RB 3

RBs case suggested hippocampal damage by itself can produce medial temporal lobe amnesia However in such cases of cerebral ischemia, it's difficult to rule out the possibility of subtle damage to other areas of the brain

Rat version of delayed non matching to sample test

Rat version of non matching to sample test played important role in assessing specific role of hippocampal damage in medial temporal lobe amnesia Coz of size and location of hippocampus, almost all studies of lesions in monkeys involved aspiration of large portions of medial temporal cortex in addition to hippocampus In rats, extraneous damage associated with aspiration lesions of hippocampus typically limited to small area of parietal neocortex Rat hippocampus small enough that can be lesioned electrolytically or with intracerebral neurotoxin injections which produces less extaneous damage

Time cells and social space

Recently, the hippocampus has been implicated in several forms of memory other than spatial memory. For example, certain cells in the hippocampus have recently been shown to code for the temporal aspects of an experience— so-called "time cells"- Eichenbaum 2014 Moreover, the hippocampus has been shown to play a role in learning about social organization ("social space") in humans- Eichenbaum 2015 and in mice

Concept cells

Recording electrodes are sometimes implanted in the brains of patients with severe epilepsy, usually as a precursor to surgery This provides an opportunity to record the activity of particular neurons in patients as they perform various tasks. Many of these electrodes are implanted in the structures of the medial temporal lobes because they are particularly susceptible to epileptic discharges

Acetylcholine 2

Reduction results from degeneration of basal forebrain- midline area located just above hypothalamus Brains main source of acetylcholine This finding coupled with finding strokes in basal forebrain area can cause amnesia led to view that acetylcholine depletion is cause if Alzheimer's amnesia Prob not only factor, damage diffuse and involved medial temporal lobes and prefrontal cortex which roles in memory- Braskie and Thompson 2013

Controversial

Relation between ischemia produced hippocampal damage and object recognition deficits in humans, monkeys and rats seems to provide strong support for theory hippocampus plays key role in object recognition memory Problem, how can ischemia produced lesions to small part of hippocampus be associated with severe deficits in performance on delayed non matching to sample test when deficits associated with total removal of hippocampus only modest Suggest damage to other brain structures contributes to amnesia observed in so following global cerebral ischemia- Mumby et al 1996

Grid cells 3

Relationship between entorhinal grid cells and hippocampal place cells is still a matter of ongoing debate- Sanders et al 2015 Two lines of evidence suggested that the responses of hippocampal place cells depend on input from entorhinal grid cells First, there is a major pathway from the entorhinal cortex to the hippocampus

Smart drugs 2

Reviews- Although nootropics are often marketed to healthy adults, most research has been done on either nonhumans or humans with memory difficulties (i.e., the elderly). The relevant research with humans tends to be of low quality, with few participants and poor controls. For each purported nootropic, there are typically a few positive findings on which the vendors focus; however, these findings are often difficult to replicate or represent very small effect sizes (see Farah, 2015)

LTP 2 and co occurence

Second, LTP develops only if the firing of the presynaptic neuron is followed by the firat ing of the postsynaptic neuron; it does not develop when the presynaptic neuron fires and the postsynaptic neuron does not, and it does not develop when the presynaptic neuron does not fire and the postsynaptic neuron does (see Bi & Poo, 2001) The co - occurrence of firing in presynaptic and postsynaptic cells is now recognized as the critical factor in LTP, and the assumption that co-occurrence is a physiological necessity for learning and memory is often referred to as Hebb ' s postulate for learning .

Grid cells 4

Second, entorhinal grid cells respond relatively reflexively to location, whereas hippocampal place cells respond to place in combination with other features of the test environment- Wills et al 2005 However, discovery that the properties of hippocampal place cells emerge in developing rat pups prior to the emergence of stable entorhinal grid cell firing challenges the idea that input from entorhinal grid cells is essential for hippocampal place cell function- Derdikman & Moser 2010 There is evidence that place cells can still function after entorhinal grid cells have been eliminated- Sanders et al 2015

Synaptic mechanisms of learning and memory- long term potentiation 3

Second, high-intensity, high-frequency stimulation lasting 10 seconds was delivered to the perforant path to induce the LTP. Third, the granule cells' responses to single pulses of low-intensity current were measured again after various delays. Figure 11.19 shows that transmission at the granule cells' synapses was still potentiated 1 week after the high-frequency stimulation.

Radial arm maze test

Several arms radiate out from a central starting chamber and same few arms baited with food each day Intact rats readily learn to visit only arms tht contain food and don't visit same arm more than once a day Ability to visit only baited arms of maze is measure of reference memory- memory for general principles and skills required to perform a task

Amnesia of Korsakoff's syndrome 2

Similar to medial temporal lobe amnesia During early stages, anterograde amnesia for explicit episodic memories most prominent symptom However as progresses, retrograde amnesia which can eventually extend back to childhood also develops Deficits in implicit memory depend on test used but in general less sever than explicit memory- Oudman et al 2011

Ambiguous and more than one

Similarly, when participants are given ambiguous human faces these concept cells respond only when the viewer perceives the concept to which the cells are attuned to- Quiroga et al 2014 Interestingly, when Jennifer Aniston neurons (concept cells) have been found to respond to more than one concept, there is usually an obvious relation between them. For example, on a second day of testing, it was discovered that the first Jennifer Aniston cell also responded to Lisa Kudrow, Jennifer Aniston's costar in the television series Friends .

Diffuse

Since diffuse, not easy identify which part of it is responsible for amnesia First hypothesis was that damage to mammillary bodies of hypothalamus responsible Subsequent studies revealed cases if ps without mammillary body damage Was damage to another part of medial diencephalon nuclei- mediodorsal nuclei of thalamus Unlikely memory deficits attributable to damage of one structure

Structures

So far focused on four neural structures that appear to play some role in the storage of memories: (1) The hippocampus and (2) the medial temporal cortex have roles in episodic memory; and (3) the mediodorsal nucleus of the thalamus and (4) the basal forebrain have been implicated in the memory deficits of Korsakoff's and Alzheimer's diseases, respectively Look at five other areas of the brain that have been implicated in memory: inferotemporal cortex, amygdala, prefrontal cortex, cerebellum, and striatum.

Study

Squire, Slater and Chace 1975- found long gradient of ECS produced retrograde amnesia Measured memory of ECS ps for TV shows that had played for only one season prior to therapy Tested each o twice in different tests- one before received 5 electroconvulsive shocks and one after Difference between before and after scores served as estimate of memory loss for events of each year

Additional support 3

Still, it is important to keep in mind that all of this evidence is indirect and that LTP as induced in the laboratory by electrical stimulation is at best a caricature of the subtle cellular events that underlie learnseemed ing and memory.

Evidence selective hippocampal damage

Strongest evidence selective hippocampal damage can cause medial temporal lobe amnesia comes from cases of transient global amnesia Transient global amnesia defined by sudden onset in absence of any obvious cause in normal adults Severe anterograde amnesia and moderate retrograde amnesia for explicit memories- Arena and Rabinstein 2015

Evolving perspective of role of hippocampus in memory

Study of ps with amnesia major limitations Many qs about neural bases of amnesia can be answered only in controlled experiments In order to identify particular structured of brain that participate in various kinds of memory, necessary to make precise lesions in various structures and to control what and when subjects learn and how and when retention tested Not feasible with humans, major effort made to develop animal models of human brain damage produced amnesia

Digit span +1 test

Test of verbal LTM Asked repeat 5 digits that read to him after 1 second intervals Repeated correctly Same 5 digits presented with 1 new added on end 6 digit sequence presented few times until got it right After 25 trials, not managed to repeat 8 digit sequence Most people can corrctly repeat 15 digits after 25 trials- Drachman and Arbit 1966

Medial temporal lobe amnesia 2

Tests that assess implicit memory- repetition priming tests eg incomplete pictures test Repetition priming tests thatvinvolve memory for words more common Fist ps are asked examine lost of words, not asked to learn or remember Later shown series of fragments of words from list and asked complete them Controls who seen words perform well Ps with amnesia perform equally well

Induction of LTP- learning

The NMDA (or N-methyl-daspartate) receptor is prominent at the synapses at which LTP is commonly studied. The nMDa receptor is a receptor for glutamate — the main excitatory neurotransmitter of the brain. An NMDA receptor does not respond maximally unless two events occur simultaneously: Glutamate must bind to it, and the postsynaptic neuron must already be partially depolarized. This dual requirement stems from the fact that the calcium channels associated with NMDA receptors allow only small numbers of calcium ions to enter the neuron unless the neuron is already depolarized when glutamate binds to the receptors; it is the influx of calcium ions that triggers the cascade of events in the postsynaptic neuron that induces LTP.

Cerebellum

The cerebellum is thought to participate in the storage of memories of learned sensorimotor skills through its various neuroplastic mechanisms (see Gao, et al 2012). Its role in the Pavlovian conditioning of the eye-blink response of rabbits has been most intensively investigated (see Freeman, 2015). Tone (conditional stimulus) is sounded just before a puff of air (unconditional stimulus) is delivered to the eye. After several trials, the tone comes to elicit an eye blink. Evidence from stimulation, recording, and lesion studies suggests that the effects of this conditioning are stored in the form of changes in the way that cerebellar neurons respond to the tone (see De Zeeuw & Ten Brinke, 2015)

Maintenance and Expression of LTP: Storage and Recall 4

The discovery of structural changes in neurons following the induction of LTP stimulated a search for a mechanism by which a neuron's activity could change its structure. This led to the discovery of numerous transcription factors (intracellular proteins that bind to DNA and influence the operation of particular genes) that were activated by neural activity (see Ryan et al., 2015).

Engram cells 2

The identification of an engram cell via optogenetics is typically a two-stage process. In the first stage, the tagging stage , the neurons that are active during the learning task are induced to express opsins while an animal engages in a particular learning task. In the second stage, the manipulate stage , the previously active neurons are now either inhibited or excited by using light to influence the activity of the opsin-tagged neurons (see Josselyn, Köhler, & Frankland, 2015

Concept cells 2

The medial temporal cortex is composed of entorhinal, perirhinal, and parahippocampal cortices Neuron fired in response to images of the actress Jennifer Aniston, but not to 80 other images- Quiroga, 2012 Other medial temporal lobe neurons were discovered that responded to other individuals known to the patients (e.g., relatives, friends, or celebrities) or to known objects, but because the first neuron responded to Jennifer Aniston, they have all been termed Jennifer aniston neurons

Prefrontal cortex 3

The prefrontal cortex is a large structure that is composed of many anatomically distinct areas that have different connections and, presumably, different functions. Functional brain-imaging studies are finding that specific complex patterns of prefrontal activity are associated with various memory functions. Some regions of prefrontal cortex seem to perform fundamental cognitive processes (e.g., attention and task management) during working memory tasks, and other regions of prefrontal cortex participate in other memory processes (e.g., Lehky & Tanaka, 2016)

Induction of LTP- learning 3

The requirement for the postsynaptic neurons to be partially depolarized when the glutamate binds to the NMDA receptors is an extremely important characteristic of conventional LTP because it permits neural networks to learn associations. If one glutaminergic neuron were to fire by itself and release its glutato mate neurotransmitter across a synapse onto the NMDA recepions, tors of a postsynaptic neuron, there would be no potentiation of transmission at that synapse because the postsynaptic cell would not fire.

Maintenance and Expression of LTP: Storage and Recall

The search for the mechanisms underlying the maintenance and expression of LTP began with attempts to determine whether these mechanisms occur in presynaptic or postsynaptic neurons. The maintenance and expression of LTP involve changes in both presynaptic and postsynaptic neurons. This discovery indicated that the mechanisms underlying the maintenance and expression of LTP are complex We still do not have satisfactory answers. However, the quest for the neural mechanisms of LTP maintenance and expression has contributed to several important discoveries

Striatum

The striatum is thought to store memories for consistent relationships between stimuli and responses— the type of memories that develop incrementally over many trials (see Graybiel & Grafton, 2015). Sometimes this striatum-based form of learning is referred to as habit formation (see O'Tousa & Grahame, 2014). Although few would disagree that the cerebellum and the striatum play a role in sensorimotor memory, there is growing evidence that these structures also play a role in certain types of memory with no obvious motor component (e.g., Maddox et al., 2005).

Gradients of retrograde amnesia and memory consolidation 2

These reverberating patterns of neural activity are susceptible to disruption by eg blow to head but eventually they induce structural changes in involved synapses which provide stable long term storage Electroconvulsive shock seemed to provide a controlled method of studying memory consolidation ECS is intense, brief, diffuse seizure inducing current administered to brain through large electrodes on scalp Rationale for using ECS to study memory consolidation was that by disrupting neural activity, would erase from storage only memories that hadn't been converted to structural synaptic changes

Case study 2

Unpredictably would sometimes recall specific experiences of no particular significance Ability to remember new experiences improved but not able to function well enough to get a job MRI of NAs brain revealed extensive medial diencephalic damage including to mediodorsal nuclei and mammillary bodies- Squire et al 1989

3 patients

Vargha-Khadem et al 1997- followed 3 ps with medial temporal lobe amnesia who experienced bilateral medial temporal lobe damage early in life Although could only remember few of experiences during daily lives, progressed through mainstream schools and acquired reasonable levels language and factual knowledge Episodic memories didn't improve- Haan et al 2006

Rat version 2

Version of delayed non matching to sample test for rats that most closely resembles monkey one developed by Mumby using Mumby box Once assumed rats couldn't perform task as complex as that required for delayed non matching to sample test but dats perform almost as well as monkeys with delays of up to 1 minute- Mumby et al 1989 Validity of rat version established by studies of effects of medial temporal lobe lesions Bilateral lesions of hippocampus, amygdala and medial temporal cortex combined produce major deficits in all but shortest retention intervals- Mumby et al 1992

Infantile amnesia

We all experience infantile amnesia ; that is, we remember virtually nothing of the events of our infancy (see Callaghan,Li, & Richardson, 2014) Newcombe et al (2000) addressed the following question: Do normal children who fail to explicitly recall or recognize things from their early childhood display preserved implicit memories for these things? The results of two experiments indicate that the answer is "yes."

Inferotemporal cortex 3

When a pair was presented, responses were first recorded in inferotemporal neurons and then in perirhinal neurons; however, when the monkeys were required to recall that pair, activity was recorded in perirhinal neurons before inferotemporal neurons. Naya and colleagues concluded that this reversed pattern of activity reflected the retrieval of visual memories from inferotemporal cortex

Concept cells 4

the most remarkable feature of Jennifer Aniston neurons is that they respond to ideas orconcepts rather than to particulars, which is why they are also known as concept cells- Quiroga, Fried, & Koch 2013 For example, a Halle Berry neuron responded to all photos of the actress, to her printed name, and to the sound of her name.