see also:

• cognition
• dementia
• the brain

• https://www.news-medical.net/news/20190826/Strong-memories-formed-by-teams-of-neurons-firing-in-synchrony.aspx
• it seems that neurons within the hippocampus have a multi-dimensionsal behaviour that responds to sensory inputs as well as keeping track of the temporal time clock sequences of memory events and thus stamping episodic memory with what, when and where components, critical to recall of these events in time sequence and within contexts ¹⁾
• ultraslow oscillatory sequences in the medial entorhinal cortex (MEC) may have the potential to couple neurons and circuits across extended time scales and serve as a template for new sequence formation during navigation and episodic memory formation ²⁾
• a new theory suggests that astrocytes have a key role in long term memory ³⁾
  • fundamental aspects of astrocyte morphology and physiology naturally lead to a dynamic, high-capacity associative memory system
  • astrocytes are necessary for forming and retrieving long-term memories (i.e., by participating in engrams)
  • astrocytes respond to neural activity on timescales spanning many orders of magnitude, from several hundred milliseconds to minutes
  • single astrocyte can form over 1 million tripartite synapses
  • astrocyte networks spatially tile the brain, forming nonoverlapping “islands”
  • astrocyte processes detect neurotransmitters in the synaptic cleft, leading to an upsurge in intracellular free calcium ions within the astrocyte process - this leads to a biochemical cascade in the astrocyte, potentially culminating in the release of gliotransmitters back into the synaptic cleft, influencing neural activity—a closed feedback loop
  • the interplay between neurons and astrocytes, spanning multiple temporal and spatial scales, underscores the relevance of astrocytes in learning and memory
  • astrocytic Ca²⁺ flux coefficients appear to be the site of memory storage, and neuron–synapse–astrocyte interactions are the mechanism of memory retrieval

• This type of memory is what allows people to temporarily hold on to and manipulate information for short periods of time such as when you ask a friend for directions to a restaurant and then keep track of the turns as you drive there.
• essentially acts as a bridge between perception (when we read a phone number) and action (when we dial that number)
• it is supported by transient patterns of neuronal communication, dependent on regions of the frontal lobe (especially dorsolateral prefrontal cortex) and the parietal lobe.
• seems to operate one step up from sensory information gathering and it extracts only the most relevant sensory information from the environment and then sums up that information in a relatively simple code ⁴⁾

• allows for long lasting memories which are embedded on an event base of what, when, where
• strong long term memories rely upon either:
  • strong emotive events (via acutely raised epinephrine, cortisol and effects in the amygdala), or,
  • repetition (hard wiring of repeated patterns via the hippocampus which is important for explicit memory and memory consolidation)
• HOWEVER, acute, prolonged or repetitive stress or glucocorticoid exposure appears to impair long term memory
  • The CA1 neurons found in the hippocampus are destroyed due to glucocorticoids decreasing the release of glucose and the reuptake of glutamate. This high level of extracellular glutamate allows calcium to enter NMDA receptors which in return kills neurons.
• long-term plastic changes in the brain, including memory formation, depend on permanent functional epigenetic alterations in neurons, rather than temporary voltage spikes and formation depends on both the activation of memory promoting genes and the inhibition of memory suppressor genes primarily via DNA methylation/demethylation.
• long term memory formation requires neuronal reprogramming of gene expression
  • initial neuronal activation
    • neuronal signals are pre-processed in various areas of the brain and generally require attention to be then directed to the hippocampus for storage
    • In the hippocampus 20%-30% of principal neurons are engaged by a given experience
    • Signals from the outside environment can cause immediate phosphorylation (activation) of a protein in the cytoplasm of a neuron.
    • The RAF-MEK-ERK kinase cascade is a chain of kinases (proteins that phosphorylate other proteins) in the neuronal cytoplasm that communicates a signal from the surface of a neuron to its nucleus.
    • Increased phosphorylated ERK (pERK) is found in the nucleus within 2 minutes following both brief and sustained neuronal activity.
    • Once in the nucleus, pERK rapidly phosphorylates the transcription factor protein ELK-1.
    • ELK-1 primarily controls immediate-early genes (IEGs), all of which have low levels of basal transcription but can reach high levels after stimulation.
    • Within 7.5 minutes after neural activation, enhancers that target promoter regions of IEGs begin transcribing their enhancer RNAs (eRNAs). The enhancers with attached eRNAs interact with their targeted IEGs and promote their transcription.
  • Immediate early genes (IEGs) such as EGR1, FOS, and ARC, are defined as genes that are expressed rapidly and transiently in response to a stimulus.
    • IEGs encode inducible transcription factor proteins that act as messengers to couple short-term neuronal activity with long-term altered gene transcription patterns in the neuron
    • Inhibition of expression of a neuronal IEG interferes with forming memories
    • EGR1, is particularly important in demethylation of genes, facilitating their expression. EGR1 recruits TET1 proteins that initiate DNA cytosine demethylation at promoter regions to allow expression of neuronal genes needed for memory formation.
  • Enhancer regions of the genome are key elements of this process. Enhancers are DNA sequences that are often tens of thousands of nucleotides distant along the DNA sequence from their target promoters but never-the-less cooperate with their target promoter DNA sequences to control target gene transcription. Chromosome loops bring enhancers to promoters.
    • Transcription factor proteins are associated with enhancer DNA sequences. Such transcription factors are essential to activate RNA polymerases that are bound to promoters of the target genes.
  • Modulation and termination of IEG activity to avoid over-production
    • For proper formation of memory, the IEG proteins must not be over-produced. Adjacent to the TOP2B protein on the promoter of the IEG genes, there are also proteins of the DNA repair pathway called non-homologous end joining (NHEJ).
    • Within 2 hours of formation of TOP2B-induced breaks in IEG promoters, NHEJ seals the breaks and IEG transcriptions return to their low basal levels.
  • demethylation of genes
    • The next step in memory formation is initiation of demethylation of cytosines at many genes, carried out by TET1 enzymes. TET1 can carry out 3 steps on cytosine methylated at its 5 position if the cytosine is followed by a guanine (a 5-mCpG site).
    • When the IEG EGR1 is expressed, the EGR1 proteins produced recruit (firmly associate with) TET1 proteins and the EGR1 proteins bring TET1s to about 595 sites in the genome where TET1s convert 5-mCpGs to 5-hmCpGs.
    • At the same time, in addition to conversion of 5-mCpG to 5-hmCpG at many genes, new methylations at CpG sites occur at many other genes. DNA methyltransferase 3A2 (DNMT3A2) is an immediate early gene. The protein for which it codes, DNMT3A2, can methylate cytosine at a CpG site to form 5-mCpG. The expression of DNMT3A2 in neurons can be induced by sustained synaptic activity. The locations of the new methylations appear to be governed by histone modifications.
    • Reactive oxygen species (ROS) also have a role in forming long-term memories and have a role in demethylation of cytosine. Oxidation of guanine in DNA by reactive oxygen species preferentially occurs at CpG sites in which the cytosine is methylated, to form 5mC-p-8-OHdG.
      • The enzyme primarily responsible for the excision of 8-OHdG by the process of base excision repair is 8-oxoguanine glycosylase (OGG1). However, OGG1, which targets and associates with 8-OHdG, has also been shown to have a role in mouse adaptive behavior. This implies a physiologically relevant role for 8-OHdG combined with OGG1 in cognition in the adult brain.
      • Upon oxidative alteration of neuronal DNA, OGG1 appears to have a role in selectively activating oxidatively altered neuronal genes through attracting TET1 to demethylate the 5mCs in their promoters.
  • transfer from hippocampus to anterior cingulate cortex for long term storage
    • These methylations and initiated demethylations in the hippocampus are the basis of the short term memory of the event. However, over a period of 4 weeks, the methylation and initiated demethylation patterns are transferred, by a process not yet understood, to the anterior cingulate cortex where long term memories are stored.
  • consolidation
    • It is thought that during slow wave sleep, the hippocampus replays the events of the day for the neocortex. The neocortex then reviews, rehearses and processes memories, which moves them into long-term memory.
    • Sleep deprivation can lead to reduced retention of memories, or false memories as the memories are not properly transferred to long-term memory.
    • Repeated imagining of events can result in false memories.
  • reconsolidation
    • Memory reconsolidation is when previously consolidated memories are recalled or retrieved from long-term memory to your active consciousness. Memories can thus be further strengthened and added to but there is also risk of manipulation involved and thus the memory is malleable and at risk of being inaccurate.
    • Memory that has undergone strong training, intentional or not, appears to be less likely to be changed during reconsolidation.
  • transfer from nucleus to dendrites
    • After a memorable event occurs many mRNAs are up-regulated or down-regulated in the nuclei of neurons within the hippocampus, anterior cingulate cortex and lateral amygdala. Nuclear mRNA transcripts acquire a protein coat composed of cap- and RNA-binding proteins that allow nuclear export to the cytoplasm.
    • Neurons have mechanisms that enable transcription events initiated in the nucleus to rapidly trigger protein synthesis at distant synaptic surfaces including packaging mRNA into neuronal granules for transport to sites of translation. Neuronal granules harbor translationally silenced mRNAs that are transported to dendritic synapses at dendritic spines, where they are released and translated in response to specific exogenous stimuli.
    • The neuronal granules travel down the dendrite at about 5 µ/s and are directed to their synapses by the 3′ untranslated regions of the mRNA in the granules.
    • Approx. 2500 mRNAs are localized to the dendrites and axons of hippocampal pyramidal neurons and more than 450 transcripts are enriched in excitatory presynaptic nerve terminals (dendritic spines).
    • These synaptic junctions are the basis of synaptic plasticity which is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity and plays an important role in learning and memory.
• recall
  • appears to involve six brain regions: (1) the prefrontal cortex, particularly on the right hemisphere; (2) the hippocampal and parahippocampal regions of the medial temporal lobe; (3) the anterior cingulate cortex; (4) the posterior midline area that includes posterior cingulate, retrosplenial (see retrosplenial region), precuneus, and cuneus regions; (5) the inferior parietal cortex, especially on the right hemisphere; and (6) the cerebellum, particularly on the left.
  • recall may be involuntary in response to a cue such as a smell, sound or word, and include PTSD responses, Déjà vu (Already seen), Jamais vu (Never Seen), and Déjà entendu (Already Heard).
  • recall may be transiently impaired for a specific recall such as a tip of the tongue (TOT) state.
  • recall of learned information can be improved with use of mnemonics and other cognitive strategies
• see Epigenet Insights. 2022; DNA Methylation and Establishing Memory