Behavioral epigenetics

Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal (including human) behavior. It seeks to explain how nurture shapes nature, where nature refers to biological heredity and nurture refers to virtually everything that occurs during the life-span (e.g., social-experience, diet and nutrition, and exposure to toxins). Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health.

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. These epigenetic changes can influence the growth of neurons in the developing brain as well as modify the activity of neurons in the adult brain. Together, these epigenetic changes in neuron structure and function can have a marked influence on an organism's behavior.

Background

In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity which are ''not'' caused by changes in the DNA sequence; the term can also be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.

Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA.

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".

Histone modification changes the way that DNA is packaged into chromosomes. These changes impact how genes are expressed.

Epigenetics has a strong influence on the development of an organism and can alter the expression of individual traits. Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span. Because some epigenetic modifications can be passed from one generation to the next, subsequent generations may be affected by the epigenetic changes that took place in the parents.

Discovery

The first documented example of epigenetics affecting behavior was provided by Michael Meaney and Moshe Szyf. While working at McGill University in Montréal in 2004, they discovered that the type and amount of nurturing a mother rat provides in the early weeks of the rat's infancy determines how that rat responds to stress later in life. This stress sensitivity was linked to a down-regulation in the expression of the glucocorticoid receptor in the brain. In turn, this down-regulation was found to be a consequence of the extent of methylation in the promoter region of the glucocorticoid receptor gene. Immediately after birth, Meaney and Szyf found that methyl groups repress the glucocorticoid receptor gene in all rat pups, making the gene unable to unwind from the histone in order to be transcribed, causing a decreased stress response. Nurturing behaviours from the mother rat were found to stimulate activation of stress signalling pathways that remove methyl groups from DNA. This releases the tightly wound gene, exposing it for transcription. The glucocorticoid gene is activated, resulting in lowered stress response. Rat pups that receive a less nurturing upbringing are more sensitive to stress throughout their life-span.

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.

Research into epigenetics in psychology

Anxiety and risk-taking

In a small clinical study in humans published in 2008, epigenetic differences were linked to differences in risk-taking and reactions to stress in monozygotic twins. The study identified twins with different life paths, wherein one twin displayed risk-taking behaviours, and the other displayed risk-averse behaviours. Epigenetic differences in DNA methylation of the CpG islands proximal to the DLX1 gene correlated with the differing behavior. The authors of the twin study noted that despite the associations between epigenetic markers and differences personality traits, epigenetics cannot predict complex decision-making processes like career selection.

Stress

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.

Studies in rats have shown correlations between maternal care in terms of the parental licking of offspring and epigenetic changes. A high level of licking results in a long-term reduction in stress response as measured behaviorally and biochemically in elements of the hypothalamic-pituitary-adrenal axis (HPA). Further, decreased DNA methylation of the glucocorticoid receptor gene were found in offspring that experienced a high level of licking; the glucorticoid receptor plays a key role in regulating the HPA. The opposite is found in offspring that experienced low levels of licking, and when pups are switched, the epigenetic changes are reversed. This research provides evidence for an underlying epigenetic mechanism. Further support comes from experiments with the same setup, using drugs that can increase or decrease methylation. Finally, epigenetic variations in parental care can be passed down from one generation to the next, from mother to female offspring. Female offspring who received increased parental care (i.e., high licking) became mothers who engaged in high licking and offspring who received less licking became mothers who engaged in less licking.

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. 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. The findings were independent of whether the mothers were being pharmaceutically treated for depression.

Recent research has also shown the relationship of methylation of the maternal glucocorticoid receptor and maternal neural activity in response to mother-infant interactions on video. Longitudinal follow-up of those infants will be important to understand the impact of early caregiving in this high-risk population on child epigenetics and behavior.

Cognition

Learning and memory

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.

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. 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.

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.

Considerable further research into long-term memory illuminated the molecular mechanisms by which methylations are established or removed, as reviewed in 2022. These mechanisms include, for instance, signal-responsive TOP2B-induced double-strand breaks in immediate early genes. More than 100 DNA double-strand breaks occur, both in the hippocampus and in the medial prefrontal cortex (mPFC), in two peaks, at 10 minutes and at 30 minutes after contextual fear conditioning. This appears to be earlier than the DNA methylations and demethylations of neuron DNA in the hippocampus that were measured at one hour and 24 hours after contextual fear conditioning.

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

One immediate early gene newly transcribed after a double-strand break is EGR1. EGR1 is an important transcription factor in memory formation. It has an essential role in brain neuron epigenetic reprogramming. EGR1 recruits the TET1 protein that initiates a pathway of DNA demethylation. Removing DNA methylation marks allows the activation of downstream genes (see Regulation of gene expression#Regulation of transcription in learning and memory. EGR1 brings TET1 to promoter sites of genes that need to be demethylated and activated (transcribed) during memory formation. EGR-1, together with TET1, is employed in programming the distribution of DNA demethylation sites on brain DNA during memory formation and in long-term neuronal plasticity.

DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity. 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. 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.

In another mechanism reviewed in 2022, 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 cognition, in terms of learning and memory; environmental enrichment correlated with increased histone acetylation, and verification by administering histone deacetylase inhibitors induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. Research has also linked learning and long-term memory formation to reversible epigenetic changes in the hippocampus and cortex in animals with normal-functioning, non-damaged brains. In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.

Psychopathology and mental health

Drug addiction

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

Even short-term substance abuse can produce long-lasting epigenetic changes in the brain of rodents, via DNA methylation and histone modification. Epigenetic modifications have been observed in studies on rodents involving ethanol, nicotine, cocaine, amphetamine, methamphetamine and opiates. 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 (e.g., in the nucleus accumbens). 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. 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. These alterations may be long-term, as is evidenced in smokers who still possess nicotine-related epigenetic changes ten years after cessation