Memory

Question 1

What did Hebb mean by a cell assembly?

Answer 1

If the inputs to a system cause the same pattern of activity to occur repeatedly, the set of active elements constituting that pattern will become increasingly strongly interassociated. That is, each element will tend to turn on every other element [..]. To put it another way, the pattern as a whole will become ‘auto- associated’. We may call a learned (auto- associated) pattern an engram”

In simple terms he was stating that“Cells that fire together, wire together”

Question 2

Define briefly the term “long term potentiation” or “LTP”

Answer 2

Long term potentiation is the activity dependent, sustained increase in synaptic strength between neurons. Long term potentiation (LTP) was first described in the hippocampus by Bliss and Lomo in 1973. Their seminal studies resulted in the now widely accepted belief that this increase in synaptic strength is the cellular correlate of memory formation.

LTP can otherwise be worded as an increase in the synaptic response to a baseline stimulus. This increase is usually seen following tetanic stimulation (a burst of high frequency stimulation, usually at 100 Hz). As AMPA receptors are the main drivers of excitatory transmission, this usually equates to increased AMPA receptor insertion and increased AMPA receptor phosphorylation, resulting in an increased AMPA receptor conductance.

Question 3

Explain the “classic” mechanism behind LTP. How does this fulfil one of Hebb’s postulates?

Answer 3

“Classic” LTP requires the activation of the NMDA receptor (NMDAR) on the postsynaptic membrane, which opens a channel to allow Ca2+ ions to enter the cell. The NMDAR acts as a coincidence detector of presynaptic and postsynaptic activity, as the channel opening requires not only the binding of glutamate (released by the presynaptic cell” but also the removal of the Mg2+ block which only occurs when the postsynaptic cell depolarises. This property allows NMDAR-dependent LTP to fulfil Hebb’s postulate, which stipulated that the connection strength between two neurons should increase if the presynaptic neurons continually causes the postsynaptic neuron to fire. This is summarised by his maxim that “cells that fire together wire together”(Hebb, 1949).

Question 4

Why is it thought that memory formation requires protein synthesis?

Answer 4

It was initially demonstrated that behavioural memories are abolished by protein synthesis blockers by Flexner et al., 1963. As a result it was thought that memory formation must require protein synthesis. Only recently however, it has been found how protein synthesis contributes to memory formation. Various studies have delineated temporal phases of LTP. It is thought that LTP has an early phase, which is independent of protein synthesis and a late phase which requires it. The late phase of LTP has been further subcategorised into two stages by Kelleher et al in 2004. Their experiments which compare the kinetic effects of transcriptional (actinomycin D) and translational blockade (anisomycin) on L-LTP confirmed this temporal dissociation, defining an early translation-dependent, transcription-independent phase of L-LTP during the initial 60–90 min following induction and a subsequent transcription- and translation-dependent phase of L-LTP.

Question 5

What is thought to underlie the two stages of L-LTP?

Answer 5

LTP2 is transcription-independent and translation-dependent, whereas LTP3 is transcription-dependent and translation-dependent.

The explanation for this difference in the inhibition kinetics is that the early effect of translational inhibition reflects the rapid translation of preexisting mRNAs, while the delayed effect of transcriptional inhibition reflects the time needed for the synthesis, processing, transport, and translation of newly synthesized mRNA.

(Kelleher, et al, 2004)

Question 6

Is protein synthesis required for memory consolidation and reconsolidation as well as formation of memory (L-LTP)?

Answer 6

Agnihotri et al in 2004 showed that blocking protein synthesis in the brain of mice does not affect short-term stability of newly formed hippocampal place fields but abolishes stability in the long term. As a result inhibiting protein synthesis prevents the consolidation of place cell maps. This shows that place fields parallel the late-phase of long-term potentiation in requiring the synthesis of new proteins for consolidation.

However their experiments showed that inhibitingprotein synthesis does not affect the recall of previously established fields in a familiar environment, indicating that recall and therefore reconsolidation is not protein synthesis-dependent.

Question 7

What are the proteins synthesised during memory formation and consolidation used for?

Answer 7

This protein synthesis is for building dendritic spines! This was demonstrated by Engert and Bonhoeffer in 1999. They combined a local superfusion technique with two-photon imaging, and showed that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.

Question 8

What is a criticism of the synaptic theory of memory? (That memory is formed from LTP)

Answer 8

A criticism of the synaptic theory of memory is that dendritic spines how constant turnover. Spine numbers are affected by overall sensory input levels, motor activity, even the estrous cycle in female rats. It is still not clear how, given these processes, the ‘engram’ can be located in dendritic spines. However it has been shown that neocortical dendritic spines have a heightened permanency relative to those in the hippocampus (Yang et al., 2009), which gives an explanation as to why spine turnover in the hippocampus does not result in memory loss.

Question 9

Is there evidence linking dendritic spines and memory?

Answer 9

A strong relationship between dendritic spine density in the hippocampus and memory has been demonstrated using different behavioral assessments. The acquisition of new memories in a conditioning paradigm is associated with increased spine density in CA1 pyramidal cells in adult rats (Leuner et al., 2003). Performance on two different spatial memory tasks, the Morris water maze and object placement, is associated with a higher dendritic spine density on pyramidal cells in CA1 (Moser et al., 1994) suggesting that there is a morphological substrate for memory.In addition, existing spines in the hippocampus undergo structural alterations that result in LTP (Jedlicka et al., 2008, Leuner et al., 2003). However it should be noted that at present it is impossible to determine whether increased dendritic spine density is the cause or result of improved hippocampal dependent memory in the aforementioned animal studies.

Question 10

There is variability in how long LTP lasts. What evidence is there that L-LTP may involve more than one set of mechanisms that determine its persistence?

Answer 10

As previously stated, the early phase of LTP- LTP1 is protein-synthesis independent, whereas the late phase of LTP is protein synthesis dependent. L-LTP can be further subcategorised into LTP2 and LTP3. LTP2 is the early translation-dependent, transcription-independent phase of L-LTP and LTP3 is the subsequent transcription- and translation-dependent phase of L-LTP. This is shown by LTP decay curves by Abraham and Otani in 1991 demonstrating that LTP may involve more than one set of mechnaims that detremine its perisistence. (LTP1 decays faster than LTP2 and LTP2 decays faster than LTP3).More recently these mechanisms have been identified and shown by (Kelleher, et al, 2004).

Question 11

What can explain the variablity in the peristence of LTP apart from how the differences in protein synthesis?

Answer 11

Many things must affect it but lecturer is going to focus on the NT dopamine.

In 2003, Li et al showed that exposure to a novel spatial environment promoted long term potentiation (LTP) at CA1 synapses in the rat hippocampus. They found that the brief exposure lowered the threshold for the induction of LTP but this was dependent on the activation of D1/D5 receptors. These findings support an important role for dopamine-regulated synaptic plasticity in the storage of unpredicted information in the CA1 area.

Dopamine is also thought to modulate memory consolidation. McNamara et al., 2014 found using an optogenic technique to stimulate VTA DA neurons that project to the hippocmapus in mice exploring novel environments improved the later recall of neural representations of space and stabilized memory performance. One theory of how dopamine contributes to improving memory recall is the synaptic tagging and capture theory (Frey & Morris, 1997. It is thought that dopamine may “tag” the synapse so that when proteins are synthesized they can be captured by the tagged synapse and used to stabilize the early plasticity changes allowing consolidation to occur.

Question 12

Explain the terms memory consolidation and systems consolidation?

Answer 12

Memory consolidation refers to the process by which a temporary, labile memory is transformed into a more stable, long lasting form. For example, the term is commonly used to describe events at the synaptic/cellular level (e.g., protein synthesis and LTP), which stabilize synaptic plasticity within hours after learning. In contrast, systems consolidation, refers to gradual reorganization of information in the hippocampus to the neocortex, and is a process that occurs within long-term memory itself (Squire and Alvarez, 1995). Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. E.g. patient HM showed retrograde amnesia for events in his 20s, but not from his childhood.

Question 13

Briefly describe the two models that predict the necessity of the hippocampus for retrieval of remote memories.

Answer 13

The Standard Model of Systems Consolidation (SMSC) and Multiple Trace Theory (MTT)

The first is the Standard Model of Systems Consolidation (SMSC: Squire and Alvarez, 1995), a widely influential view in the field. The SMSC holds that the initial memory trace is encoded both in the hippocampus and in the cortex, though the cortex is itself unable to initially support the memory. Rather, the hippocampus is critical in early encoding stages. As a function of time, replay, and retrieval, the hippocampus “teaches” the cortex the memory trace such that the associative connectivity between the individual elements of the cortical memory increase in strength over time. After the memory has been consolidated, the hippocampus is no longer required for retrieval. This is based on the large body of evidence that synapses change much more rapidly and dynamically in the hippocampus than they do in cortex (Yang et al 2009). Thus, the SMSC predicts that the hippocampus is not required for the retrieval of remote memories, only recent ones that have not yet been consolidated.

The competing theory, known as Multiple Trace Theory (MTT), was proposed by Nadel and Moscovitch (1997) as an alternative to the standard model. Unlike the SMSC, MTT proposed that the hippocampus has an important role in the retrieval of all episodic memories, including remote ones. Similar to the SMSC, MTT also proposed that memories are encoded in hippocampal-neocortical networks, but that each reactivation resulted in a different trace in the hippocampus. Hippocampal-bound traces are presumed to be contextual and rich in spatial and temporal details, while cortical-bound traces are presumed to be semantic and largely context-free. Thus, retrieval of remote semantic memories does not require the hippocampus, however, retrieval of remote episodic memories always does, irrespective of the age of the memory.

Question 14

Evidence for and against Standard Model of Systems Consolidation (SMSC)

Answer 14

Aspects of hippocampal lesion-induced amnesia can be found in Pavlovian fear conditioning, in which a tone conditional stimulus (CS) is paired with a shock unconditional stimulus (US) several times in a novel context. Rats trained in this manner develop a fear of both the tone and training context, which we measure as freezing, an adaptive species-specific defense reaction.

Contextual fear acquisition is thought to involve spatial learning (Nadel and Willner, 1980), and therefore support hippocampal involvement in contextual fear conditioning.

Kim and Fanselow (1992) gave rats tone-shock pairings before the animals received a lesion of the hippocampu. In this study, hippocampal lesions made 1 day after training produced a near-complete deficit in contextual fear, while sparing tone freezing. In contrast, lesions made 28 days after training failed to produce a reliable deficit. Hippocampal lesions produced a selective and time-limited retrograde amnesia of contextual fear. This led us to suggest that the hippocampus plays a temporary role in the formation of some aspects of contextual fear memory, which must be- come independent of the hippocampus over some time period after training.

As lesioning is an extremely invasive technique, which may produce damage in non-lesioned areas, and is permanent (no possibility to run a within-subject, baseline-manipulation-baseline design). Can optogenetics give us a new perspective?

Interestingly, it is important to note that recent studies have raised the possibility that even remote memory (memories that have consolidated to other brain regions) remains hippocampus-dependent (Goshen et al. 2011). This study does not support the standard model of systems consolidation.

Question 15

It is assumed that memory “stored” in the hippocmapus is vulnerable to disruption but is safe when “stored” in the neocortex. Give an example where this has been shown not to be the case.

Answer 15

It was shown ex vivo that engram cells from the dentate gyrus established preferential connections with engram cells in the downstream hippocampal CA3 region. Remarkably, this preferential connectivity was maintained in mice rendered amnesic by treatment with PSI within the consolidation window, suggesting that memory storage may survive retrograde amnesia in the form of a neural connectivity pattern. Ryan et al 2015

Question 16

What is PTSD? What has been used to model it?

Answer 16

Post-traumatic stress disorder (PTSD) is a mental disorder associated with traumatic memory, including fear memory. In experimental animals, Pavlovian fear conditioning has been widely used as a model of PTSD. The most widely used fear conditioning paradigms are based on a contextual or cued fear conditioning task, in which a rodent learns the association (i.e., training) between the conditioned stimulus (CS), such as a chamber (context) or a tone (cue). When re-exposed to the chamber (context) or the tone (cue), the conditioned rodent shows immobile freezing (fear) responses by retrieving the conditioned fear memory.

Question 17

Explain what is meant by reconsolidation of memory.

Answer 17

When a memory is retrieved, it returns to a labile state similar to that existing immediately after memory formation (destabilization) (Nader et al. 2000). Re-stabilization is necessary for the memory to be re- stored. This re-stabilization process requires protein synthesis like cellular consolidation does this; therefore, the process of re-storing memories is referred to as reconsolidation (Nader et al. 2000).

Question 18

Why does memory reconsolidate? Is reconsolidation just like consolidation or does it involve unique mechanisms?

Answer 18

What is the advantage of having established memories become labile and then restored? The general advantage of reconsolidation is that it provides the ability to respond in a flexible and adaptive manner to the continuous changing environment. There is evidence that shows reconsolidation allows changes in memory strength, and so some people believe that reconsolidation mediates the updating of memory content.

Question 19

Which studies provided evidence that memory retrieval caused it to become labile and vulnerable to disruption and therefore need to be reconsolidated?

Answer 19

In 1968, Misanin and colleagues published a study that shattered the tenets of standard theories of memory consolidation. On a first day of training, they taught rats to fear an auditory cue (conditioned stimulus, CS), by pairing the presentation of that cue with the administration of a footshock (unconditioned stimulus, US) in a Pavlovian fear conditioning procedure. The animals exhibited a clear fear response to the tone CS when it was presented two days later, indicating that they had indeed a memory associating the tone with footshock. In keeping with previous research, Misanin et al. (1968) also observed that such a conditioned fear response on day 3 was absent in animals that had received a strong electroconvulsive shock (ECS) shortly after the initial tone-footshock training on day 1. This was consistent with the idea that during initial consolidation, memory traces are sensitive to disruption so that an intervention like ECS that interrupts the consolidation process will yield retrospective amnesia for the events immediately preceding that intervention (Duncan 1949). More importantly, Misanin et al. went on to show that in animals where consolidation had been allowed to proceed without interference on day 1 and a fear memory was supposedly in place, similar amnesia could be induced by giving the animals ECS not during consolidation on the initial training day but on day 2, right after they were presented with a reminder for the fear memory acquired on day 1 (i.e., a presentation of the auditory CS, without the US). So, if these animals were tested on day 3, they showed no indication of having a fear memory involving the auditory cue, just like the animals that had received ECS right after the initial CS-US training. This observation squarely contradicted the idea that memories are impervious to disruption after consolidation has completed and represented the first demonstration of experimentally induced amnesia for a previously established, reactivated fear memory.

Following these observations it was proposed that that memory retrieval can lead to the destabilization of a consolidated memory trace, inducing the need for a time-limited process of protein-synthesis dependent reconsolidation (Sara 2000).

Evidence for the reconsolidation hypothesis came from studies showing that pharmacological blockade of protein synthesis processes that had been demonstrated to be critical for fear memory consolidation, through infusion in the amygdala of a protein synthesis inhibitor like anisomycin (Nader et al. 2000) prevented expression of that memory the next day.

Question 20

Two states of memory? How does this provide a window for pharmacological intervention to treat pathogenic memories in anxiety and PTSD?

Answer 20

Sara 2000, stated a memory can be in one of two states, an active, unstable state (in the minutes to hours after it has been acquired or reactivated by retrieval) or an inactive, stable state (after consolidation and in the absence of reactivation). In the active state, the memory trace requires DNA transcription and protein synthesis to be (re)stabilized into an inactive state. The active state thus offers a window of opportunity to interfere with the integrity of the memory trace, through the disruption of those neurobiological processes.

Question 21

Evidence for and against the succesful erasure of memory after retrieval of it.

Answer 21

Early evidence suggests that this may work. Rubin et al. (1969) and Rubin (1976) treated patients suffering from either hallucinations, delusions, major depression, or OCD with electroconvulsive therapy (ECT). In contrast to other studies that administered ECT when the subjects were anaesthetized, Rubin and colleagues kept the patients awake and directed them to focus on the objects of their compulsions or hallucinations. This experimental procedure was thought to reactivate the neural mechanisms mediating those memories when the ECT was delivered. All of the subjects were reportedly “cured” of their condition. The fact that ECT was effective only when the memories were presumed to be reactivated, but not when the memory reactivation was omitted (i.e., when the patient was anesthetized), suggests, in principle, that reconsolidation occurs in humans.

More recent candidate treatments tend to be less intrusive than ECT (Kroes et al. 2014). For example, β-adrenergic antagonists, such as propranolol, have now been used to target reconsolidation. Brunet et al (2008, J. Psych. Res.) ‘reactivated’ the traumatic memories of PTSD patients (with a variety of etiologies) using a ‘scripting exercise’, then administered propranolol. A week later, patients heart rate and skin conductance were measured while they listened to their own scripts: a decrease in skin conductance and heart rate was found.

However, this remains controversial. For example, Wood et al (2015, Psychiatry Res) failed to replicate this result with a group of US army veterans diagnosed with PTSD. Critically, they point out that Brunet et al failed to control for general effects of propranolol, as opposed to propranolol + reactivation

One possibility is that propranolol preferentially affects the implicit emotional aspects of memory stored through circuits involving the amygdala (but perhaps other circuits as well) without significantly affecting the content or representation of complex memories stored via the medial temporal lobe circuits necessary for explicit memory. This difference may represent an advantage when the goal is to weaken the emotional significance without decreasing the cognitive representation. More studies are needed to understand the target mechanisms and the effects and/or boundary conditions of propranolol in clinical applications.

Furthermore work from Ryan et al 2015 suggest that the amnesia induced by the administration of a putative protein synthesis inhibitor or other amnestic agents does not refelct erasure of the memory trace (see also Ryan et al. 2015). Instead, the authors argue, as a result of the memory being brought back in an active state, the internal state provoked by drug administration at the time of memory retrieval will become integrated into the memory representation. This in turn renders later expression of the memory state-dependent, so that in the absence of the internal drug state amnesia occurs; this amnesia is lifted when the drug state is recreated by re-administration.

Question 22

What was wrong with the Brunet et al 2008 and Wood et al 2015 study?

Answer 22

It should be noted that both studies had several important limitations, such as small sample sizes and lack of control groups for either the effects of reactivation or general drug effects

Question 23

Give a reason as to why some studies failed to get rid of the unwanted memory even within the reconsolidation window time frame?

Answer 23

An important consideration regarding these findings is that reconsolidation effects may be subject to certain boundary conditions such as the age and strength of a memory, thus making interference with fear memories more complicated (Duvarci et al., 2006; Wang et al., 2009). Moreover, many of these conditioning protocols use a single-trial, producing a relatively weak fear memory which may be more susceptible to blockade than fear memories existing in patients with PTSD.

Question 24

Name a particularly important boundary condition which may result in difficulty in treating PTSD?

Answer 24

Another boundary condition is the finding that reactivation of a memory is necessary, but not sufficient, to destabilize a memory. Whether or not a memory trace is destabilized may, at least partly, depend on whether there is something to be learned, i.e. whether there is novel or conflicting information resulting in the need for an update of the memory.

This may be governed by prediction error, i.e. a mismatch between what is expected and what occurs For example, one study (Sevenster et al.,2013) showed that in the case that a certain stimulus (CS) always predicted a shock (UCS), a single unreinforced presentation of the CS led to a violation of predictions and triggered memory destabilization. However, in the case of uncertainty (e.g. the stimulus was only reinforced in 50% of the trials during encoding), more unreinforced trials were needed to create a mismatch with what was expected and hence destablise the memory. Similarly, older memories may require additional retrieval procedures for updating to take place (Inda et al.,2011), as do individual differences such as high exposure to chronic stress (Hoffman et al.,2015).