Study of the genetics of human<unk>  is in its infancy though many genes have been investigated for their association to<unk>  in humans and non-human animals. A notable initial success was the association of APOE with<unk>  dysfunction in Alzheimer's disease. The search for genes associated with normally varying<unk>  continues. One of the first candidates for normal variation in<unk>  is the protein KIBRA, which appears to be associated with the rate at which material is forgotten over a delay period. There has been some evidence that<unk> es are stored in the nucleus of neurons. Genetic underpinnings Several genes, proteins and enzymes have been extensively researched for their association with<unk> . Long-term<unk> , unlike short-term<unk> , is dependent upon the synthesis of new proteins. 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. For more information, see long-term potentiation (LTP). One of the newly synthesized proteins in LTP is also critical for maintaining long-term<unk> . 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<unk> es, without affecting short-term<unk>  or, once the inhibitor is eliminated, the ability to encode and store new long-term<unk> es is restored. Also, BDNF is important for the persistence of long-term<unk> es. The long-term stabilization of synaptic changes is also determined by a parallel increase of pre- and postsynaptic structures such as axonal bouton, dendritic spine and postsynaptic density. On the molecular level, an increase of the postsynaptic scaffolding proteins PSD-95 and HOMER1c has been shown to correlate with the stabilization of synaptic enlargement. The cAMP response element-binding protein (CREB) is a transcription factor which is believed to be important in consolidating short-term to long-term<unk> es, and which is believed to be downregulated in Alzheimer's disease. DNA methylation and demethylation Rats exposed to an intense learning event may retain a life-long<unk>  of the event, even after a single training session. The long-term<unk>  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<unk>  seems to take place in the anterior cingulate cortex. When such an exposure was experimentally applied, more than 5,000 differently methylated DNA regions appeared in the hippocampus neuronal genome of the rats at one and at 24 hours after training. These alterations in methylation pattern occurred at many genes that were down-regulated, often due to the formation of new 5-methylcytosine sites in CpG rich regions of the genome. Furthermore, many other genes were upregulated, likely often due to hypomethylation. Hypomethylation often results from the removal of methyl groups from previously existing 5-methylcytosines in DNA. Demethylation is carried out by several proteins acting in concert, including the TET enzymes as well as enzymes of the DNA base excision repair pathway (see Epigenetics in learning and<unk> . The pattern of induced and repressed genes in brain neurons subsequent to an intense learning event likely provides the molecular basis for a long-term<unk>  of the event. Epigenetics Studies of the molecular basis for<unk>  formation indicate that epigenetic mechanisms operating in brain neurons play a central role in determining this capability. Key epigenetic mechanisms involved in<unk>  include the methylation and demethylation of neuronal DNA, as well as modifications of histone proteins including methylations, acetylations and deacetylations. Stimulation of brain activity in<unk>  formation is often accompanied by the generation of damage in neuronal DNA that is followed by repair associated with persistent epigenetic alterations. In particular the DNA repair processes of non-homologous end joining and base excision repair are employed in<unk>  formation. Role of DNA Topoisomerase II Beta in learning and<unk>  During a new learning experience, a set of genes is rapidly expressed in the brain. This induced gene expression is considered to be essential for processing the information being learned. Such genes are referred to as immediate early genes (IEGs). DNA Topoisomerase II Beta (TOP2B) activity is essential for the expression of IEGs in a type of learning experience in mice termed associative fear<unk> . Such a learning experience appears to rapidly trigger TOP2B to induce double-strand breaks in the promoter DNA of IEG genes that function in neuroplasticity. Repair of these induced breaks is associated with DNA demethylation of IEG gene promoters allowing immediate expression of these IEG genes. Regulatory sequence in a promoter at a transcription start site with a paused RNA polymerase and a TOP2B-induced double-strand break Brain regions involved in<unk>  formation including medial prefrontal cortex (mPFC) The double-strand breaks that are induced during a learning experience are not immediately repaired. About 600 regulatory sequences in promoters and about 800 regulatory sequences in enhancers appear to depend on double strand breaks initiated by topoisomerase 2-beta (TOP2B) for activation. The induction of particular double-strand breaks are specific with respect to their inducing signal. When neurons are activated in vitro, just 22 of TOP2B-induced double-strand breaks occur in their genomes. Such TOP2B-induced double-strand breaks are accompanied by at least four enzymes of the non-homologous end joining (NHEJ) DNA repair pathway (DNA-PKcs, KU70, KU80, and DNA LIGASE IV) (see Figure). These enzymes repair the double-strand breaks within about 15 minutes to two hours. The double-strand breaks in the promoter are thus associated with TOP2B and at least these four repair enzymes. These proteins are present simultaneously on a single promoter nucleosome (there are about 147 nucleotides in the DNA sequence wrapped around a single nucleosome) located near the transcription start site of their target gene. The double-strand break introduced by TOP2B apparently frees the part of the promoter at an RNA polymerase-bound transcription start site to physically move to its associated enhancer (see regulatory sequence). This allows the enhancer, with its bound transcription factors and mediator proteins, to directly interact with the RNA polymerase paused at the transcription start site to start transcription. Contextual fear conditioning in the mouse causes the mouse to have a long-term<unk>  and fear of the location in which it occurred. Contextual fear conditioning causes hundreds of DSBs in mouse brain medial prefrontal cortex (mPFC) and hippocampus neurons (see Figure: Brain regions involved in<unk>  formation}. These DSBs predominately activate genes involved in synaptic processes, that are important for learning and<unk> .
Memory
Working memory
Episodic memory
Gross processing
Associative memory 
Motor planning
Serial memory processing
Visuospatial function