memory mechanisms and consolidation 06/05 Flashcards
What is the evidence that some molecular mechanism occurs after a memory is formed to ‘consolidate’ it?
Contextual fear training in mice given an anisomyocin injection (protein synthesis blocker) allows normal creation of a short term memory up to one hr after training(inferred from freezing) - however there is no long term memory. This suggests that some process occurs after the memory formation that allows the memory to become long lasting.
Further experiments injecting anisomyocin at different time points revealed that there are consolidation windows. For example, only if anisomyocin was injected at 0hrs or 4hrs was LTM impaired.
What is CREB?
cAMP response element binding protein. It is important in consolidation of memories. It is a cellular transcription factor, activated by different kinases such as CAMKIV, PKA etc. Many signalling processes can coverge to activate it.
It leads to expression of genes such as c-fos and BDNF, leading to memory consolidation. For example, abolishing CREB in mutant mice leads to loss of LTM fear conditioning, although STM (a few minutes after) is retained.
However, CREB also regulates thousands of genes - making it quite difficult to locate the downstream effects leading to memory consolidation. RNA sequencing technology can identify which genes are regulated during memory consolidation and whether they are regulated by CREB.
What are immediate early genes?
Immediate early genes (IEGs) are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli - in the case of neurons this usually refers to a high intensity stimuli, such as tetanic stimulation, training or seizure.
Immediate early genes have two main types:
- *1. Transcription factors** such as cfos, zif268. These have both been shown to very important in memory consolidation.
- *2. Signalling proteins** such as BDNF
Contextual fear training normally results in upregulation of cfos, zif268 and nu7 in the hippocampus and basolateral amygdala of mouse. This is impaired in the CAMKII T268A mouse model, in which autophosphorylation of CAMKII inhibitory subunit is impaired (and thus making CAMKII only active when ca++ is high and ca++/cam binds). This mutation is known to block LTP induction and reduce learning of other episodic hippocampal dependent memories such as place cell field retention and morris water maze learning.
An example of sex differences in memory consolidation
BDNF is an immediate early signalling gene,
In male mice, it is upregulated after training.
Female mice show much higher baseline levels of BDNF (at all stages of oestrogen cycle), and it is downregulated after training.
Knocking out CAMKKa (phosphorylates CAMK1) abolishes training induced changes of BDNF in males, and has no effect on females.
Males and females may therefore use different mechanisms to consolidate memory.
What is systems consolidation?
Systems consolidation refers memory consolidation that occurs at the level of brain structures and systems. Retrieval processes change over time, and these time scales differ considerably to that of cellular consolidation.
It is clear that systems consolidation involves an increased retreival from the cortex. It reamins controversial as to whether the memory becomes hippocampus indepedent.
What did the mouse hippocampal lesion study show about systems consolidation?
Hippocampal lesioning 1 day after contextual fear training (when cellular consolidation is believed to already be complete) leads to an extensive loss of the fear memory. This effect is observed also at 7 and 14 days (but less so). At 28 days, lesioning the hippocampus has no effect on the fear memory. This suggests that after 28 days, the memory is no longer hippocampally depedent - perhaps because the memory has been transferred to another brain structure (the necortex). These results were corrorborated with deoxyglucose post mortem radiographic imaging studies that indicated that new memory retreival increases metabolic activity in hippocampus, whereas remote memory retrieval increases metabolic activity in the primarily in the cortex. This would constiute a form of systems consolidation.
It could also be interpreted that two memories are formed - 1 hippocampal, 1 cortical - and that the cortex memory forms more slowly, and over time the cortical memory tends to be retrieved from cortex rather than hippocampus.
What have optogenetic studies revealed about systems consolidation?
Optogenetics were used in mice, to inhibit the CA1 at different time points thoughout contextual fear training and recall.
Inhibition during training prevented formation of a fear memory, implying that contextual fear memory is depedent on a memory mechanism occuring in CA1.
If the mouse was trained without the light, and then tested with the light 24hrs later, then a fear response was not shown. This implied that 24hrs after the memory formed, the CA1 region is still required for storage/recall.
If the mouse was trained without the light and then tested with the light 28weeks later, the fear response is not shown. if the light is then switched off, the fear response is shown. This suggests that even 28weeks later, the memory storage/retrieval is still hippocampal depedent.
This contradicts the findings of the lesion studies on mice, which suggested that hippocampus is not required for storage/retreival of fear memory 28days later. It has been suggested that the lesion study allowed for some kind of compensation mechanism.
What is memory reconsolidation?
After a formed memory is retrieved, it becomes labile once more and requires restabilising. This is thought to be important in ‘updating’.
This has been shown by fear conditioning, which results in freezing response when tested 24hr later. If anisomyocin is injected after the test, then there is no freezing response observed another 24hrs later.
Importantly, if anisomyocin is injected without the test then the memory is retained - therefore protein synthesis is not required simply to maintain a memory, but only to ‘reconsolidate’ it once it has become reactivated.
It is believed that the destabilisation occuring is due to a protein degradation process, where ubiqitin systems are switched on at the synpase. Protein synthesis is thus required to replace these proteins and keep the synpase/memory
What is the evidence that memory reconsolidation is not simply a recapitulation of consolidation?
Both share upregulation of some immediate early genes, however there are also immediate early genes that are upregulated in consolidation but not reconsolidation. - suggesting different mechanisms.
Experiments have also targeted the mRNA of immediate early genes during consolidation and reconsolidation. They have found that BDNF but not zif268 is required for consolidation. The opposite is true for reconsolidation
What is memory extinction?
This when a memory becomes supressed. For example, fear conditioning is used to train an mouse, which will then show freezing when they are exposed that context. However, if they are re-exposed to that context for a long period of time with no shock, then they will lose the freezing response.
Extinct memories may also be spontaneously recovered. This when animals who are rexposed to the learning situation have rapid re-aquisition of the behavioural response which occurs much faster than the original learning process.
What is the evidence that memory loss during reconsolidation and memory extinction are not the same process?
Delivering anisomyocin during re-exposure to the fear context prevents the extinction of the memory. This is because extinction is a learning process, which requires formation of new memories to suppress the old memories - thus requiring protein synthesis.
This is the opposite effect of reconsolidation. Memories are lost if anisomyocin is given during reconsolidation.
Both processes require protein synthesis, but the outcome is the opposite.
Molecular mechanisms underlying extinction remain unclear.
What is cellular consolidation?
These are cellular processes underpinning the formation of long term memory. They are involving:
- gene trasncription
- gene regulation
- epigenetic processes
- protein synthesis
These processes appear to be stabilising synpases in order to keep the memory.
What are epigenetics and how may they be involved in memory consolidation?
Heritable changes to the gene expression that do not alter the genome themselves. Epigenetic modifactions often involve changes to histones that alter their affinity for DNA, thus opening up or closing access to genes by transcription factors. Common histone modifications include:
- *methylation** - this can repress or increase expression
- *acetylation** - generally increases expression
- *phosphorylation** - generally increases expression.
This is likely one of the mechanisms involved in cellular consolidation, where rapid and late gene expression changes occur. Epigenetic changes can be tracked using antibodies for specific alterations. It has been shown that transient epigenetic changes occur around 1-2 hours after learning experiences.
CREB binds to CBP (creb binding protein), acting as a co-activator. CBP has intrinsic histone acetyltransferase activity and can thus regulate the expression of genes.
CAMK activation also results in downstream epigenetic changes.
