Epigenetic mechanisms underlying learning and the inheritance of learned behaviors

Abstract

Gene expression and regulation is an important sculptor of the behavior of organisms. Epigenetic mechanisms regulate gene expression not by altering the genetic alphabet but rather by the addition of chemical modifications to proteins associated with the alphabet or of methyl marks to the alphabet itself. Being dynamic, epigenetic mechanisms of gene regulation serve as an important bridge between environmental stimuli and genotype. In this review, we outline epigenetic mechanisms by which gene expression is regulated in animals and humans. Using fear learning as a framework, we then delineate how such mechanisms underlie learning and stress responsiveness. Finally, we discuss how epigenetic mechanisms might inform us about the transgenerational inheritance of behavioral traits that are being increasingly reported.

Figure 1. Overview of Epigenetic Regulatory Mechanisms

This schematic diagram demonstrates the primary known functions of the different enzymes referred to within the review. (A) Histone acetyltransferases (HAT) add acetyl groups to lysine residues on histone tails, generally associated with relaxing wound DNA and promoting transcription. (B) Histone deacetylases (HDAC) remove those acetyl groups, and inhibit transcription. (C-D) Histone methylation is mediated by histone methyltansferases (HMTs) which add methyl groups to lysine residues on histone tails and is reversed by histone demethylases (HDMs). The impact of histone methylation on transcription largely depends on the lysines and state of methylation (mono-, di-, tri). (E) DNA methyltransferases (DNMT) add methyl groups are added to the cytosines of CpG islands, resulting in a 5-methylcytosine state, and is generally associated with DNA silencing. (F) Active demethylation has recently been associated with Tet protein mediated hydroxylation of 5-methylcytosine, resulting in 5-hydroxymethylcytosine and has been found to facilitate transcription. (G) Schematic diagram of miRNA mediated inhibition of gene translation and mRNA degradation as examples for epigenetic regulation by small non-coding RNAs.

Figure 2. How Epigenetic Regulation of Neuronal Gene Expression May alter Neuronal Plasticity and Activity, Resulting in Memory Formation

This schematic diagram illustrates various mechanisms, supported by published data, by which coordinated cellular activity leads to altered intracellular signaling, with resultant epigenetic alterations at the levels of noncoding RNA, histone regulation and DNA methylation. Together such changes alter regulation of gene expression, resulting in postsynaptic changes at the levels of spine density, receptor sensitivity and intrinsic excitability, etc., as well as providing the substrates for altered presynaptic structural and functional change. The changing of the neuronal state at the level of epigenetic gene regulation interacts with local determinants related to synaptic connectivity and circuit activity, which together alter neurocircuitry dynamics underlying memory formation.

Figure 3. Epigenetics and Stress Responding: Example of the FKBP5 GeneFKBP5 regulates the HPA axis and is epigenetically modified by childhood abuse in a genotype dependent manner

(A) FKBP5 is a co-chaperone of the glucocorticoid receptor (GR), binding via hsp90 and reducing its affinity for cortisol thus providing a ultra short feedback loop to limit HPA activation. In response to cortisol binding, FKBP5 is replaced by FKBP4 which facilitates the translocation of the GR-complex into the nucleus where the GR binds to glucocorticoid response elements (GRE). Among other stress responsive genes, FKBP5 transcription and translation is increased via intronic response elements, which confers higher GR resistance, serving as an ultra-short negative feedback loop on GR sensitivity. (B) Epigenetic regulation of FKBP5 in response to childhood abuse. The genetic predisposition in FKBP5 determines the three-dimensional organization of the FKBP5 locus and the stress dependent transcriptional activation of the gene with higher mRNA expression in risk allele carriers due to an increased interaction of distal GREs. In response to childhood abuse, carriers of the protective genotype maintain a stable epigenetic profile whereas in risk allele carriers, trauma induces a demethylation in GRE with further de-repression of FKBP5 transcriptional activation. The resulting HPA axis deregulation contributes to the development of psychiatric disorders (adapted from Klengel et al, 2013).

Figure 4. Epigenetic Transmission of Learned Olfactory Behavior

Training an F0 generation of mice in an olfactory fear conditioning paradigm wherein a particular odor (orange lines) is paired with a mild foot-shock (blue jagged shape) results in a sensitivity toward that odor in the F0 generation that also extends into the F1 and F2 generations that have never been exposed to that odor before. When Acetophenone (sensed by M71 receptors) is used as the conditioning odor in the F0 generation, there are more M71-expressing olfactory sensory neurons in the nose of these animals that then results in more axons converging into larger glomeruli in the olfactory bulbs of the brain. This enhanced neuroanatomical representation for M71 is also observed in the F1 and F2 generation, and of note, in a generation created via in vitro fertilization (IVF). The persistence of sensitivity to the F0 conditioned odors in F1, F2, and cross-fostered (not depicted) generations implies a biological inheritance of information, as is the case made by the observation of more M71 representation in F1, F2, and IVF-derived generations. We observe decreased DNA methylation around the M71 receptor gene in sperm of the F0 and F1 generations, potentially associated with the enhanced representation for M71 neurons in the descendant generations.