Behavioral epigenetics

Behavioral epigenetics is the field of study examining the role of

Epigenetic gene regulation involves changes other than to the sequence of DNA and includes changes to histones (proteins around which DNA is wrapped) and DNA methylation.^[10][4][11] These epigenetic changes can influence the growth of neurons in the developing brain^[12] as well as modify the activity of neurons in the adult brain.^[13][14] Together, these epigenetic changes in neuron structure and function are thought to have an influence on behavior.^[1]

In

DNA methylation turns a gene "off" – it results in the inability of genetic information to be read from DNA; removing the methyl tag can turn the gene back "on".^[21][22]

Histone modification changes the way that DNA is packaged into chromosomes. These changes impact how genes are expressed.^[23]{{

Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span.^[4][24]

The first documented example of epigenetics affecting behavior was provided by

This pioneering work in rodents has been difficult to replicate in humans because of a general lack of availability of human brain tissue for measurement of epigenetic changes.[1]

A 2010 review discussed the role of DNA methylation in memory formation and storage, but the precise mechanisms involving neuronal function, memory, and methylation reversal remained unclear at the time.^[26]

Further research investigated the molecular basis for long-term memory. By 2015 it had become clear that long-term memory requires gene transcription activation and de novo protein synthesis.^[27] Long-term memory formation depends on both the activation of memory promoting genes and the inhibition of memory suppressor genes, and DNA methylation/DNA demethylation was found to be a major mechanism for achieving this dual regulation.^[28]

Rats with a new, strong long-term memory due to contextual fear conditioning have reduced expression of about 1,000 genes and increased expression of about 500 genes in the hippocampus of the brain 24 hours after training, thus exhibiting modified expression of 9.17% of the rat hippocampal genome. Reduced gene expressions were associated with methylations of those genes and hypomethylation was found for genes involved in synaptic transmission and neuronal differentiation.^[29]

Further research into long-term memory has shed light on the molecular mechanisms by which methylation is created or removed, as reviewed in 2022.

The double strand breaks occur at known memory-related immediate early genes (among other genes) in neurons after neuron activation.^[32][31] These double-strand breaks allow the genes to be transcribed and then translated into active proteins.

One

DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity.^[34] DNMTs bind to DNA and methylate cytosines at particular locations in the genome. If this methylation is prevented by DNMT inhibitors, then memories do not form.^[35] If DNMT3A2 is over-expressed in the hippocampus of young adult mice it converts a weak learning experience into long-term memory and also enhances fear memory formation.^[28]

In another mechanism reviewed in 2022,^[30] the messenger RNAs of many genes that had been subjected to methylation-controlled increases or decreases are transported by neural granules (messenger RNPs) to the dendritic spines. At these locations the messenger RNAs can be translated into the proteins that control signaling at neuronal synapses.

Studies in rodents have found that the environment exerts an influence on epigenetic changes related to

Due to the stress that can be placed on individuals can increase levels of anxiety and the way the epigenetics are responding in relation to the individual. Epigenetics investigate how alterations upon environment and behavior can affect the way in which genes operate.[40] Within research, it's know that majority of epigenetic modifications identified have been involved with anxiety-like phenotypes that involve genes that regulate the hypothalamic-pituitary adrenal axis which results to the way our bodies respond to stress that we endure as people.^[41] Epigenetics is altered by many influences, whether it be genetic and or environmental. Within the prenatal times it is evident that through changes of DNA methylation, that maternal and pre-maternal distress have been connected to modifications in the fetal HPA axis.^[42] This demonstrates that the link between our development, stress and anxiety a mother can feel during this time creates a linkage in the response of how the epigenetic may be altered in the response of the HPA axis. Linkage of the impacts of childhood trauma in connection with epigenetic and anxiety, in that there is a change in DNA methylation process, increasing the chances of neuroendocrine damage to likely occur. In relation, the neuroendocrine damage induces the state of depression, making it mentally unstable for a person to possibly perform their daily activities. The Brain-derived neurotropic factor (BDNF) is known to change its state because of epigenetic mechanisms and contributes to the alters within the development process necessary for the brain of us individuals.^[43] Alterations within the epigenetic process can be treated using different types clinical procedures, by targeting specific changes and the treating them with the proper sort of care.^[43]

Animal and human studies have found correlations between poor care during infancy and epigenetic changes that correlate with long-term impairments that result from neglect.^[44][45][46]

Studies in rats have shown correlations between maternal care in terms of the parental licking of offspring and epigenetic changes.

In humans, a small clinical research study showed the relationship between prenatal exposure to maternal mood and genetic expression resulting in increased reactivity to stress in offspring.^[4] Three groups of infants were examined: those born to mothers medicated for depression with serotonin reuptake inhibitors; those born to depressed mothers not being treated for depression; and those born to non-depressed mothers. Prenatal exposure to depressed/anxious mood was associated with increased DNA methylation at the glucocorticoid receptor gene and to increased HPA axis stress reactivity.^[44] The findings were independent of whether the mothers were being pharmaceutically treated for depression.^[44]

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction v t e Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1] This diagram depicts the signaling events in the nuclear factor kappa B), it induces an addictive state.[51][52]

Environmental and epigenetic influences seem to work together to increase the risk of addiction.^[54] For example, environmental stress has been shown to increase the risk of substance abuse.^[55] In an attempt to cope with stress, alcohol and drugs can be used as an escape.^[56] Once substance abuse commences, however, epigenetic alterations may further exacerbate the biological and behavioural changes associated with addiction.^[54]

Even short-term substance abuse can produce long-lasting epigenetic changes in the brain of rodents,^[54] via DNA methylation and histone modification.^[19] Epigenetic modifications have been observed in studies on rodents involving ethanol, nicotine, cocaine, amphetamine, methamphetamine and opiates.^[4] Specifically, these epigenetic changes modify gene expression, which in turn increases the vulnerability of an individual to engage in repeated substance overdose in the future. In turn, increased substance abuse results in even greater epigenetic changes in various components of a rodent's reward system^[54] (e.g., in the nucleus accumbens^[57]). Hence, a cycle emerges whereby changes in areas of the reward system contribute to the long-lasting neural and behavioural changes associated with the increased likelihood of addiction, the maintenance of addiction and relapse.^[54] In humans, alcohol consumption has been shown to produce epigenetic changes that contribute to the increased craving of alcohol. As such, epigenetic modifications may play a part in the progression from the controlled intake to the loss of control of alcohol consumption.^[58] These alterations may be long-term, as is evidenced in smokers who still possess nicotine-related epigenetic changes ten years after cessation.^[59] Therefore, epigenetic modifications^[54] may account for some of the behavioural changes generally associated with addiction. These include: repetitive habits that increase the risk of disease, and personal and social problems; need for immediate gratification; high rates of relapse following treatment; and, the feeling of loss of control.^[60]

Evidence for relevant epigenetic changes came from human studies involving alcohol,

Epigenetic changes including hypomethylation of glutamatergic genes (i.e., NMDA-receptor-subunit gene

The causes of major depressive disorder (MDD) are poorly understood from a neuroscience perspective.^[72] The epigenetic changes leading to changes in glucocorticoid receptor expression and its effect on the HPA stress system discussed above, have also been applied to attempts to understand MDD.^[73]

Much of the work in animal models has focused on the indirect downregulation of

Epigenetics may be relevant to aspects of psychopathic behaviour through methylation and histone modification.[77] These processes are heritable but can also be influenced by environmental factors such as smoking and abuse.^[78] Epigenetics may be one of the mechanisms through which the environment can impact the expression of the genome.^[79] Studies have also linked methylation of genes associated with nicotine and alcohol dependence in women, ADHD, and drug abuse.^[80][81][82] It is probable that epigenetic regulation as well as methylation profiling will play an increasingly important role in the study of the play between the environment and genetics of psychopaths.^[83]

Several studies have indicated DNA cytosine methylation linked to the social behavior of insects, such as honeybees and ants. In honeybees, when nurse bee switched from her in-hive tasks to out foraging, cytosine methylation marks are changing. When a forager bee was reversed to do nurse duties, the cytosine methylation marks were also reversed.^[84] Knocking down the DNMT3 in the larvae changed the worker to queen-like phenotype.^[85] Queen and worker are two distinguish castes with different morphology, behavior, and physiology. Studies in DNMT3 silencing also indicated DNA methylation may regulate gene alternative splicing and pre-mRNA maturation.^[86]

Many researchers contribute information to the Human Epigenome Consortium.^[87] The aim of future research is to reprogram epigenetic changes to help with addiction, mental illness, age related changes,^[2] memory decline, and other issues.^[1] However, the sheer volume of consortium-based data makes analysis difficult.^[2] Most studies also focus on one gene.^[88] In actuality, many genes and interactions between them likely contribute to individual differences in personality, behaviour and health.^[89] As social scientists often work with many variables, determining the number of affected genes also poses methodological challenges. More collaboration between medical researchers, geneticists and social scientists has been advocated to increase knowledge in this field of study.^[90]

Limited access to human brain tissue poses a challenge to conducting human research.^[2] Not yet knowing if epigenetic changes in the blood and (non-brain) tissues parallel modifications in the brain, places even greater reliance on brain research.^[87] Although some epigenetic studies have translated findings from animals to humans,^[91] some researchers caution about the extrapolation of animal studies to humans.^[1] One view notes that when animal studies do not consider how the subcellular and cellular components, organs and the entire individual interact with the influences of the environment, results are too reductive to explain behaviour.^[89]

Some researchers note that epigenetic perspectives will likely be incorporated into pharmacological treatments.^[8] Others caution that more research is necessary as drugs are known to modify the activity of multiple genes and may, therefore, cause serious side effects.^[1] However, the ultimate goal is to find patterns of epigenetic changes that can be targeted to treat mental illness, and reverse the effects of childhood stressors, for example. If such treatable patterns eventually become well-established, the inability to access brains in living humans to identify them poses an obstacle to pharmacological treatment.^[87] Future research may also focus on epigenetic changes that mediate the impact of psychotherapy on personality and behaviour.^[44]

Most epigenetic research is correlational; it merely establishes associations. More experimental research is necessary to help establish causation.^[92] Lack of resources has also limited the number of intergenerational studies.^[2] Therefore, advancing longitudinal^[90] and multigenerational, experience-dependent studies will be critical to further understanding the role of epigenetics in psychology.^[5]

• Behavioral genetics
• Behavioral neuroscience
• Epigenetics of anxiety and stress-related disorders
• Evolutionary neuroscience
• Neuroscience
• Personality psychology