Editing Long-term memory (section)

==Biological underpinnings at the cellular level==
Long-term memory, unlike short-term memory, is dependent upon the synthesis of new proteins.<ref>{{cite book | author = Costa-Mattioli M, Sonenberg N | year = 2008| volume = 169 | pages = 81–95 | pmid = 18394469 | doi=10.1016/S0079-6123(07)00005-2| last2 = Sonenberg | title = Essence of Memory | chapter = Chapter 5 Translational control of gene expression: A molecular switch for memory storage | series = Progress in Brain Research | isbn = 9780444531643 | url = https://escholarship.mcgill.ca/concern/articles/r207tv251 }}</ref> This occurs within the cellular body, and concerns the particular transmitters, receptors, and new synapse pathways that reinforce the communicative strength between neurons. The production of new proteins devoted to synapse reinforcement is triggered after the release of certain signaling substances (such as calcium within hippocampal neurons) in the cell. In the case of hippocampal cells, this release is dependent upon the expulsion of magnesium (a binding molecule) that is expelled after significant and repetitive synaptic signaling. The temporary expulsion of magnesium frees NMDA receptors to release calcium in the cell, a signal that leads to gene transcription and the construction of reinforcing proteins.<ref>Neihoff, Debra (2005) "The Language of Life 'How cells Communicate in Health and Disease'" Speak Memory, 210–223.</ref> For more information, see [[long-term potentiation]] (LTP).

One of the newly synthesized proteins in LTP is also critical for maintaining LTM. This protein is an autonomously active form of the enzyme [[protein kinase C]] (PKC), known as [[PKMζ]]. PKMζ maintains the activity-dependent enhancement of synaptic strength and inhibiting PKMζ erases established long-term memories, without affecting short-term memory or, once the inhibitor is eliminated, the ability to encode and store new long-term memories is restored.

Also, [[BDNF]] is important for the persistence of long-term memories.<ref>{{Cite journal
 | last1 = Bekinschtein | first1 = Pedro | last2 = Cammarota | first2=Martin | last3 = Katche | first3 = Cynthia | last4 = Slipczuk | first4 = Leandro | last5 = Rossato | first5 = Janine I. | last6 = Goldin | first6 = Andrea | last7 = Izquierdo | first7 = Ivan | last8 = Medina | first8 = Jorge H.
 | title = BDNF is essential to promote persistence of long-term memory storage
 | journal = [[Proceedings of the National Academy of Sciences of the USA]]
 | doi = 10.1073/pnas.0711863105
 | date = February 2008
 | volume = 105
 | issue = 7
 | pages = 2711–2716
 | pmid = 18263738
 | pmc = 2268201
| bibcode = 2008PNAS..105.2711B | doi-access = free }}</ref>

The long-term stabilization of synaptic changes is also determined by a parallel increase of pre- and postsynaptic structures such as [[Axon terminal|synaptic boutons]], [[dendritic spine]]s, and [[postsynaptic density]].<ref name="stabilization_plasticity">
{{cite journal
  |last=Meyer
  |first=D.
  |author2=Bonhoeffer T., and Scheuss V.
  |year=2014
  |title=Balance and Stability of Synaptic Structures during Synaptic Plasticity 
  |journal=Neuron
  |volume=82
  |issue=2
  |pages=430–443
  |doi=10.1016/j.neuron.2014.02.031
  |pmid=24742464|doi-access=free
  }}</ref>
On the molecular level, an increase of the postsynaptic scaffolding proteins [[PSD-95]] and [[HOMER1]]c has been shown to correlate with the stabilization of synaptic enlargement.<ref name="stabilization_plasticity" />

The cAMP response element-binding protein ([[CREB]]) is a [[transcription factor]] which is believed to be important in consolidating short- to long-term memories, and which is believed to be downregulated in Alzheimer's disease.<ref>{{cite journal | doi=10.1016/S0959-4388(96)80082-1 | pmid=8725970 | volume=6 | issue=2 | title=CREB and the formation of long-term memory | journal=Current Opinion in Neurobiology | pages=264–268| year=1996 | last1=Yin | first1=Jerry CP | last2=Tully | first2=Timothy | s2cid=22788405}}</ref>

===[[DNA methylation]] and [[DNA demethylation|demethylation]]===

Rats exposed to an intense learning event may retain a life-long memory of the event, even after a single training session. The LTM of such an event appears to be initially stored in the hippocampus, but this storage is transient. Much of the long-term storage of the memory seems to take place in the [[anterior cingulate cortex]].<ref>{{cite journal | pmid = 15131309 | doi=10.1126/science.1094804 | volume=304 | title=The involvement of the anterior cingulate cortex in remote contextual fear memory | year=2004 | journal=Science | pages=881–3 | last1 = Frankland | first1 = PW | last2 = Bontempi | first2 = B | last3 = Talton | first3 = LE | last4 = Kaczmarek | first4 = L | last5 = Silva | first5 = AJ | issue=5672 | bibcode = 2004Sci...304..881F| s2cid=15893863 }}</ref> When such an exposure was experimentally applied, more than 5,000 differently methylated DNA regions appeared in the [[hippocampus]] [[neuron]]al [[genome]] of the rats at one and at 24 hours after training.<ref>{{cite journal | pmid = 28620075 | doi=10.1101/lm.045112.117 | volume=24 | title=Experience-dependent epigenomic reorganization in the hippocampus | pmc=5473107 | year=2017 | journal=Learn Mem | pages=278–288 | last1 = Duke | first1 = CG | last2 = Kennedy | first2 = AJ | last3 = Gavin | first3 = CF | last4 = Day | first4 = JJ | last5 = Sweatt | first5 = JD| issue=7 }}</ref> These alterations in methylation pattern occurred at many [[gene]]s that were [[downregulation and upregulation|down-regulated]], often due to the formation of new [[5-methylcytosine]] sites in CpG rich regions of the genome. Furthermore, many other genes were [[downregulation and upregulation|upregulated]], likely often due to hypomethylation. Hypomethylation often results from the removal of methyl groups from previously existing [[5-methylcytosine]]s in DNA. Demethylation is carried out by several proteins acting in concert, including [[TET enzymes]] as well as enzymes of the DNA [[base excision repair]] pathway (see [[Epigenetics in learning and memory]]). The pattern of induced and repressed genes in brain neurons subsequent to an intense learning event likely provides the molecular basis for a LTM of the event.