Behavioral epigenetics

Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal and 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 are thought to have an influence on 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. Genetic activity can be influenced by environmental factors, as well as parenting styles, diet and even social interactions.

Examples of mechanisms that produce such changes are DNA methylation and histone modification, both alter how genes are expressed without changing the underlying DNA sequence and both are also essential for learning and memory. 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.{{

Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span.{{cite journal , vauthors = Campbell IC, Mill J, Uher R, Schmidt U , title = Eating disorders, gene-environment interactions and epigenetics , journal = Neuroscience and Biobehavioral Reviews , volume = 35 , issue = 3 , pages = 784–93 , date = Jan 2011 , pmid = 20888360 , doi = 10.1016/j.neubiorev.2010.09.012 , s2cid = 24599095

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.

Cognition

Learning and memory

{{main, Epigenetics in 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.{{cite journal , vauthors = Day JJ, Sweatt JD , title = DNA methylation and memory formation , journal = Nature Neuroscience , volume = 13 , issue = 11 , pages = 1319–23 , date = Nov 2010 , pmid = 20975755 , pmc = 3130618 , doi = 10.1038/nn.2666

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.{{cite journal , vauthors=Alberini CM, Kandel ER , title=The regulation of transcription in memory consolidation , journal=Cold Spring Harb Perspect Biol , volume=7 , issue=1 , pages=a021741 , date=December 2014 , pmid=25475090 , pmc=4292167 , doi=10.1101/cshperspect.a021741 , url= 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.{{cite journal , vauthors=Oliveira AM , title=DNA methylation: a permissive mark in memory formation and maintenance , journal=Learn Mem , volume=23 , issue=10 , pages=587–93 , date=October 2016 , pmid=27634149 , pmc=5026210 , doi=10.1101/lm.042739.116 , url=

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.{{cite journal , vauthors=Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD , title=Experience-dependent epigenomic reorganization in the hippocampus , journal=Learn Mem , volume=24 , issue=7 , pages=278–288 , date=July 2017 , pmid=28620075 , pmc=5473107 , doi=10.1101/lm.045112.117 , url=

Further research into long-term memory has shed light on the molecular mechanisms by which methylation is created or removed, as reviewed in 2022.{{cite journal , vauthors=Bernstein C , title=DNA Methylation and Establishing Memory , journal=Epigenet Insights , volume=15 , issue= , pages=25168657211072499 , date=2022 , pmid=35098021 , pmc=8793415 , doi=10.1177/25168657211072499 , url= 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.{{cite journal , vauthors=Stott RT, Kritsky O, Tsai LH , title=Profiling DNA break sites and transcriptional changes in response to contextual fear learning , journal=PLOS ONE , volume=16 , issue=7 , pages=e0249691 , date=2021 , pmid=34197463 , pmc=8248687 , doi=10.1371/journal.pone.0249691 , bibcode=2021PLoSO..1649691S , url=, doi-access=free 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.{{cite journal , vauthors=Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH , title=Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes , journal=Cell , volume=161 , issue=7 , pages=1592–605 , date=June 2015 , pmid=26052046 , pmc=4886855 , doi=10.1016/j.cell.2015.05.032 , url= 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.{{cite journal , vauthors=Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H , title=EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity , journal=Nat Commun , volume=10 , issue=1 , pages=3892 , date=August 2019 , pmid=31467272 , pmc=6715719 , doi=10.1038/s41467-019-11905-3 , bibcode=2019NatCo..10.3892S , url= 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.{{cite journal , vauthors=Oliveira AM, Hemstedt TJ, Bading H , title=Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities , journal=Nat Neurosci , volume=15 , issue=8 , pages=1111–3 , date=July 2012 , pmid=22751036 , doi=10.1038/nn.3151 , s2cid=10590208 , url= 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.{{cite journal , vauthors=Bayraktar G, Kreutz MR , title=Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression? , journal=Neuroscientist , volume=24 , issue=2 , pages=171–185 , date=April 2018 , pmid=28513272 , pmc=5846851 , doi=10.1177/1073858417707457 , url= 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.{{cite journal , vauthors = Miller G , title = Epigenetics. The seductive allure of behavioral epigenetics , journal = Science , volume = 329 , issue = 5987 , pages = 24–7 , date = Jul 2010 , pmid = 20595592 , doi = 10.1126/science.329.5987.24 , bibcode = 2010Sci...329...24M {{cite journal , vauthors = Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH , title = Recovery of learning and memory is associated with chromatin remodelling , journal = Nature , volume = 447 , issue = 7141 , pages = 178–82 , date = May 2007 , pmid = 17468743 , doi = 10.1038/nature05772 , bibcode = 2007Natur.447..178F , s2cid = 36395789 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.{{cite journal , vauthors = Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD, Paylor RE, Lubin FD , title = Histone methylation regulates memory formation , journal = The Journal of Neuroscience , volume = 30 , issue = 10 , pages = 3589–99 , date = Mar 2010 , pmid = 20219993 , pmc = 2859898 , doi = 10.1523/JNEUROSCI.3732-09.2010 In human studies, post-mortem brains from patients with Alzheimer's dementia show high levels of histone de-acetylase.{{cite journal , vauthors = Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH , title = An epigenetic blockade of cognitive functions in the neurodegenerating brain , journal = Nature , volume = 483 , issue = 7388 , pages = 222–6 , date = Mar 2012 , pmid = 22388814 , pmc = 3498952 , doi = 10.1038/nature10849 , bibcode = 2012Natur.483..222G {{cite journal , vauthors = Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A , title = Altered histone acetylation is associated with age-dependent memory impairment in mice , journal = Science , volume = 328 , issue = 5979 , pages = 753–6 , date = May 2010 , pmid = 20448184 , doi = 10.1126/science.1186088 , bibcode = 2010Sci...328..753P , s2cid = 7370920

Psychopathology and mental health

Anxiety and risk-taking

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. 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. 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.{{Cite journal , last=Azargoonjahromi , first=Ali , date=2023-11-01 , title=The role of epigenetics in anxiety disorders , url=https://link.springer.com/article/10.1007/s11033-023-08787-6 , journal=Molecular Biology Reports , language=en , volume=50 , issue=11 , pages=9625–9636 , doi=10.1007/s11033-023-08787-6 , issn=1573-4978, url-access=subscription 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.{{Cite journal , last=Arce , first=Luis , last2=Serrano , first2=Irene , date=2023-09-13 , title=Impact of childhood trauma on the epigenetics of anxiety disorder , url=https://archivespsy.com/menu-script/index.php/ACF/article/view/2193 , journal=Archives of Clinical Psychiatry , language=en , volume=50 , issue=6 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.

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.{{cite journal , vauthors=Masterpasqua F , year=2009 , title=Psychology and epigenetics , journal=Review of General Psychology , volume=13 , issue=3 , pages=194–201 , doi=10.1037/a0016301 , s2cid=35879739{{cite journal , vauthors=Szyf M, McGowan P, Meaney MJ , date=Jan 2008 , title=The social environment and the epigenome , journal=Environmental and Molecular Mutagenesis , volume=49 , issue=1 , pages=46–60 , bibcode=2008EnvMM..49...46S , doi=10.1002/em.20357 , pmid=18095330 , s2cid=18739871 , doi-access=free{{cite journal , vauthors=González-Pardo H, Pérez Álvarez M , date=Feb 2013 , title=Epigenetics and its implications for Psychology , journal=Psicothema , volume=25 , issue=1 , pages=3–12 , doi=10.7334/psicothema2012.327 , pmid=23336536 , hdl-access=free , hdl=10651/13408

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.

Drug addiction

{{Further, ΔFosB, G9a, H3K9me2#Addiction
{{Psychostimulant addiction, Colorcode=yes, align=right
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.{{cite journal , vauthors = Andersen SL, Teicher MH , title = Desperately driven and no brakes: developmental stress exposure and subsequent risk for substance abuse , journal = Neuroscience and Biobehavioral Reviews , volume = 33 , issue = 4 , pages = 516–24 , date = Apr 2009 , pmid = 18938197 , pmc = 2688959 , doi = 10.1016/j.neubiorev.2008.09.009 In an attempt to cope with stress, alcohol and drugs can be used as an escape.{{cite book , vauthors = Carver C , chapter = Coping , veditors = Baum A, Contrada RJ , title = The Handbook of Stress Science: Biology, Psychology, and Health , publisher = Springer Publishing Company , location = New York , year = 2010 , pages = 223 , isbn = 978-0-8261-1471-6 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.{{cite journal , vauthors = Maze I, Nestler EJ , title = The epigenetic landscape of addiction , journal = Annals of the New York Academy of Sciences , volume = 1216 , issue = 1, pages = 99–113 , date = Jan 2011 , pmid = 21272014 , pmc = 3071632 , doi = 10.1111/j.1749-6632.2010.05893.x , bibcode = 2011NYASA1216...99M 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{{cite journal , vauthors = Wong CC, Mill J, Fernandes C , title = Drugs and addiction: an introduction to epigenetics , journal = Addiction , volume = 106 , issue = 3 , pages = 480–9 , date = Mar 2011 , pmid = 21205049 , doi = 10.1111/j.1360-0443.2010.03321.x (e.g., in the nucleus accumbens{{cite journal , vauthors = Renthal W, Nestler EJ , title = Epigenetic mechanisms in drug addiction , journal = Trends in Molecular Medicine , volume = 14 , issue = 8 , pages = 341–50 , date = Aug 2008 , pmid = 18635399 , pmc = 2753378 , doi = 10.1016/j.molmed.2008.06.004 ). 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.{{cite journal , vauthors = Naassila M , title = Abstracts of ESBRA 2011, European Society for Biomedical Research on Alcoholism. Vienna, Austria. September 4–7, 2011 , journal = Alcohol and Alcoholism , volume = 46 , issue = Suppl 1 , pages = i1-63 , year = 2011 , pmid = 21863600 , doi = 10.1093/alcalc/agr085 , doi-access = free These alterations may be long-term, as is evidenced in smokers who still possess nicotine-related epigenetic changes ten years after cessation.{{cite journal , vauthors = Launay JM, Del Pino M, Chironi G, Callebert J, Peoc'h K, Mégnien JL, Mallet J, Simon A, Rendu F , title = Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation , journal = PLOS ONE , volume = 4 , issue = 11 , pages = e7959 , year = 2009 , pmid = 19956754 , pmc = 2775922 , doi = 10.1371/journal.pone.0007959 , bibcode = 2009PLoSO...4.7959L , doi-access = free Therefore, epigenetic modifications 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.{{cite journal , vauthors = Marlatt GA, Baer JS, Donovan DM, Kivlahan DR , title = Addictive behaviors: etiology and treatment , journal = Annual Review of Psychology , volume = 39 , pages = 223–52 , year = 1988 , pmid = 3278676 , doi = 10.1146/annurev.ps.39.020188.001255

Evidence for relevant epigenetic changes came from human studies involving alcohol,{{cite journal , vauthors = Bönsch D, Lenz B, Reulbach U, Kornhuber J, Bleich S , title = Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism , journal = Journal of Neural Transmission , volume = 111 , issue = 12 , pages = 1611–6 , date = Dec 2004 , pmid = 15565495 , doi = 10.1007/s00702-004-0232-x , s2cid = 10692616 nicotine, and opiate abuse. Evidence for epigenetic changes stemming from amphetamine and cocaine abuse derives from animal studies. In animals, drug-related epigenetic changes in fathers have also been shown to negatively affect offspring in terms of poorer spatial working memory, decreased attention and decreased cerebral volume.{{cite journal , vauthors = He F, Lidow IA, Lidow MS , title = Consequences of paternal cocaine exposure in mice , journal = Neurotoxicology and Teratology , volume = 28 , issue = 2 , pages = 198–209 , year = 2006 , pmid = 16458479 , doi = 10.1016/j.ntt.2005.12.003

Eating disorders and obesity

{{further, ΔFosB
Epigenetic changes may help to facilitate the development and maintenance of eating disorders via influences in the early environment and throughout the life-span. Pre-natal epigenetic changes due to maternal stress, behaviour and diet may later predispose offspring to persistent, increased anxiety and anxiety disorders. These anxiety issues can precipitate the onset of eating disorders and obesity, and persist even after recovery from the eating disorders.{{cite journal , vauthors = Raney TJ, Thornton LM, Berrettini W, Brandt H, Crawford S, Fichter MM, Halmi KA, Johnson C, Kaplan AS, LaVia M, Mitchell J, Rotondo A, Strober M, Woodside DB, Kaye WH, Bulik CM , title = Influence of overanxious disorder of childhood on the expression of anorexia nervosa , journal = The International Journal of Eating Disorders , volume = 41 , issue = 4 , pages = 326–32 , date = May 2008 , pmid = 18213688 , doi = 10.1002/eat.20508 , pmc = 8048416

Epigenetic differences accumulating over the life-span may account for the incongruent differences in eating disorders observed in monozygotic twins. At puberty, sex hormones may exert epigenetic changes (via DNA methylation) on gene expression, thus accounting for higher rates of eating disorders in men as compared to women {{Citation needed, reason=A quick research on the web goes on the other direction, date=February 2023. Overall, epigenetics contribute to persistent, unregulated self-control behaviours related to the urge to binge.

Schizophrenia

{{further, Epigenetics of schizophrenia
Epigenetic changes including hypomethylation of glutamatergic genes (i.e., NMDA-receptor-subunit gene NR3B and the promoter of the AMPA-receptor-subunit gene GRIA2) in the post-mortem brains of people with schizophrenia are associated with increased levels of the neurotransmitter glutamate.{{cite book , veditors=Bronner F, Helmtrud I , title=Epigenetic Aspects of Chronic Diseases , publisher=Springer , location=Berlin , year=2011 , isbn=978-1-84882-643-4 , vauthors=Mostafavi-Abdolmaleky H, Glatt SJ, Tsuang MT , chapter=Epigenetics in Psychiatry , pages=163–174 Since glutamate is the most prevalent, fast, excitatory neurotransmitter, increased levels may result in the psychotic episodes related to schizophrenia. Epigenetic changes affecting a greater number of genes have been detected in men with schizophrenia as compared to women with the illness.{{cite journal , vauthors=Abdolmaleky HM, Thiagalingam S, Wilcox M , title=Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope , journal=American Journal of Pharmacogenomics , volume=5 , issue=3 , pages=149–60 , year=2005 , pmid=15952869 , doi=10.2165/00129785-200505030-00002, s2cid=16397510

Population studies have established a strong association linking schizophrenia in children born to older fathers.{{cite journal , vauthors = Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES , title = Advancing paternal age and the risk of schizophrenia , journal = Archives of General Psychiatry , volume = 58 , issue = 4 , pages = 361–7 , date = Apr 2001 , pmid = 11296097 , doi = 10.1001/archpsyc.58.4.361 , doi-access = free Specifically, children born to fathers over the age of 35 years are up to three times more likely to develop schizophrenia. Epigenetic dysfunction in human male sperm cells, affecting numerous genes, have been shown to increase with age. This provides a possible explanation for increased rates of the disease in men.{{cite journal , vauthors = Rutten BP, Mill J , title = Epigenetic mediation of environmental influences in major psychotic disorders , journal = Schizophrenia Bulletin , volume = 35 , issue = 6 , pages = 1045–56 , date = Nov 2009 , pmid = 19783603 , pmc = 2762629 , doi = 10.1093/schbul/sbp104 {{Failed verification, date=September 2012 To this end, toxins (e.g., air pollutants) have been shown to increase epigenetic differentiation. Animals exposed to ambient air from steel mills and highways show drastic epigenetic changes that persist after removal from the exposure.{{cite journal , vauthors = Yauk C, Polyzos A, Rowan-Carroll A, Somers CM, Godschalk RW, Van Schooten FJ, Berndt ML, Pogribny IP, Koturbash I, Williams A, Douglas GR, Kovalchuk O , title = Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 105 , issue = 2 , pages = 605–10 , date = Jan 2008 , pmid = 18195365 , pmc = 2206583 , doi = 10.1073/pnas.0705896105 , bibcode = 2008PNAS..105..605Y , doi-access = free Therefore, similar epigenetic changes in older human fathers are likely. Schizophrenia studies provide evidence that the nature versus nurture debate in the field of psychopathology should be re-evaluated to accommodate the concept that genes and the environment work in tandem. As such, many other environmental factors (e.g., nutritional deficiencies and cannabis use) have been proposed to increase the susceptibility of psychotic disorders like schizophrenia via epigenetics.

Bipolar disorder

Evidence for epigenetic modifications for bipolar disorder is unclear.{{cite journal , vauthors = McGowan PO, Kato T , title = Epigenetics in mood disorders , journal = Environmental Health and Preventive Medicine , volume = 13 , issue = 1 , pages = 16–24 , date = Jan 2008 , pmid = 19568875 , pmc = 2698240 , doi = 10.1007/s12199-007-0002-0 , bibcode = 2008EHPM...13...16M One study found hypomethylation of a gene promoter of a prefrontal lobe enzyme (i.e., membrane-bound catechol-O-methyl transferase, or COMT) in post-mortem brain samples from individuals with bipolar disorder. COMT is an enzyme that metabolizes dopamine in the synapse. These findings suggest that the hypomethylation of the promoter results in over-expression of the enzyme. In turn, this results in increased degradation of dopamine levels in the brain. These findings provide evidence that epigenetic modification in the prefrontal lobe is a risk factor for bipolar disorder.{{cite journal , vauthors = Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, Pan H, Papageorgis P, Ponte JF, Sivaraman V, Tsuang MT, Thiagalingam S , title = Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder , journal = Human Molecular Genetics , volume = 15 , issue = 21 , pages = 3132–45 , date = Nov 2006 , pmid = 16984965 , pmc = 2799943 , doi = 10.1093/hmg/ddl253 However, a second study found no epigenetic differences in post-mortem brains from bipolar individuals.{{cite journal , vauthors = Dempster EL, Mill J, Craig IW, Collier DA , title = The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression , journal = BMC Medical Genetics , volume = 7 , pages = 10 , year = 2006 , pmid = 16483362 , pmc = 1456954 , doi = 10.1186/1471-2350-7-10 , doi-access = free

Major depressive disorder

The causes of major depressive disorder (MDD) are poorly understood from a neuroscience perspective.{{cite journal , vauthors = Massart R, Mongeau R, Lanfumey L , title = Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression , journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences , volume = 367 , issue = 1601 , pages = 2485–94 , date = Sep 2012 , pmid = 22826347 , pmc = 3405682 , doi = 10.1098/rstb.2012.0212 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.{{cite journal , vauthors = Pariante CM, Lightman SL , title = The HPA axis in major depression: classical theories and new developments , journal = Trends in Neurosciences , volume = 31 , issue = 9 , pages = 464–8 , date = Sep 2008 , pmid = 18675469 , doi = 10.1016/j.tins.2008.06.006 , s2cid = 13308611

Much of the work in animal models has focused on the indirect downregulation of brain derived neurotrophic factor (BDNF) by over-activation of the stress axis.{{cite journal , vauthors = Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ , title = Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action , journal = Nature Neuroscience , volume = 9 , issue = 4 , pages = 519–25 , date = Apr 2006 , pmid = 16501568 , doi = 10.1038/nn1659 , s2cid = 21547891 {{cite journal , vauthors = Gray JD, Milner TA, McEwen BS , title = Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors , journal = Neuroscience , volume = 239 , pages = 214–27 , date = Jun 2013 , pmid = 22922121 , doi = 10.1016/j.neuroscience.2012.08.034 , pmc = 3743657 Studies in various rodent models of depression, often involving induction of stress, have found direct epigenetic modulation of BDNF as well.{{cite journal , vauthors = Hunter RG , title = Epigenetic effects of stress and corticosteroids in the brain , journal = Frontiers in Cellular Neuroscience , volume = 6 , pages = 18 , year = 2012 , pmid = 22529779 , doi = 10.3389/fncel.2012.00018 , pmc=3329877, doi-access = free

Psychopathy

Epigenetics may be relevant to aspects of psychopathic behaviour through methylation and histone modification.{{cite journal , vauthors = Jiang Y, Langley B, Lubin FD, Renthal W, Wood MA, Yasui DH, Kumar A, Nestler EJ, Akbarian S, Beckel-Mitchener AC , title = Epigenetics in the nervous system , journal = The Journal of Neuroscience , volume = 28 , issue = 46 , pages = 11753–9 , date = Nov 2008 , pmid = 19005036 , pmc = 3844836 , doi = 10.1523/JNEUROSCI.3797-08.2008 These processes are heritable but can also be influenced by environmental factors such as smoking and abuse.{{cite journal , vauthors = Philibert RA, Beach SR, Gunter TD, Brody GH, Madan A, Gerrard M , title = The effect of smoking on MAOA promoter methylation in DNA prepared from lymphoblasts and whole blood , journal = American Journal of Medical Genetics Part B , volume = 153B , issue = 2 , pages = 619–28 , date = Mar 2010 , pmid = 19777560 , pmc = 3694401 , doi = 10.1002/ajmg.b.31031 Epigenetics may be one of the mechanisms through which the environment can impact the expression of the genome.{{cite journal , vauthors = Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A , title = The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies , journal = American Journal of Medical Genetics Part B , volume = 147B , issue = 5 , pages = 543–9 , date = Jul 2008 , pmid = 17987668 , pmc = 3643119 , doi = 10.1002/ajmg.b.30657 Studies have also linked methylation of genes associated with nicotine and alcohol dependence in women, ADHD, and drug abuse.{{cite journal , vauthors = Philibert RA, Gunter TD, Beach SR, Brody GH, Madan A , title = MAOA methylation is associated with nicotine and alcohol dependence in women , journal = American Journal of Medical Genetics Part B , volume = 147B , issue = 5 , pages = 565–70 , date = Jul 2008 , pmid = 18454435 , pmc = 3685146 , doi = 10.1002/ajmg.b.30778 {{cite journal , vauthors = Bodnar RJ , title = Endogenous opiates and behavior: 2009 , journal = Peptides , volume = 31 , issue = 12 , pages = 2325–59 , date = Dec 2010 , pmid = 20875476 , pmc = 2693002 , doi = 10.1016/j.peptides.2010.09.016 {{cite journal , vauthors = Mill J, Petronis A , title = Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility , journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines , volume = 49 , issue = 10 , pages = 1020–30 , date = Oct 2008 , pmid = 18492038 , doi = 10.1111/j.1469-7610.2008.01909.x 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.{{cite journal , vauthors = Gunter TD, Vaughn MG, Philibert RA , title = Behavioral genetics in antisocial spectrum disorders and psychopathy: a review of the recent literature , journal = Behavioral Sciences & the Law , volume = 28 , issue = 2 , pages = 148–73 , year = 2010 , pmid = 20422643 , doi = 10.1002/bsl.923

Social insects

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.{{cite journal , vauthors = Herb BR, Wolschin F, Hansen KD, Aryee MJ, Langmead B, Irizarry R, Amdam GV, Feinberg AP , title = Reversible switching between epigenetic states in honeybee behavioral subcastes , journal = Nature Neuroscience , volume = 15 , issue = 10 , pages = 1371–3 , date = Oct 2012 , pmid = 22983211 , doi = 10.1038/nn.3218 , pmc=3518384 Knocking down the DNMT3 in the larvae changed the worker to queen-like phenotype.{{cite journal , vauthors = Kucharski R, Maleszka J, Foret S, Maleszka R , s2cid = 955740 , title = Nutritional control of reproductive status in honeybees via DNA methylation , journal = Science , volume = 319 , issue = 5871 , pages = 1827–30 , date = Mar 2008 , pmid = 18339900 , doi = 10.1126/science.1153069 , bibcode = 2008Sci...319.1827K 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.{{cite journal , vauthors = Li-Byarlay H, Li Y, Stroud H, Feng S, Newman TC, Kaneda M, Hou KK, Worley KC, Elsik CG, Wickline SA, Jacobsen SE, Ma J, Robinson GE , title = RNA interference knockdown of DNA methyl-transferase 3 affects gene alternative splicing in the honey bee , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 110 , issue = 31 , pages = 12750–5 , date = Jul 2013 , pmid = 23852726 , doi = 10.1073/pnas.1310735110 , pmc=3732956, bibcode = 2013PNAS..11012750L , doi-access = free

Limitations and future direction

Many researchers contribute information to the Human Epigenome Consortium.{{cite journal , vauthors = Albert PR , title = Epigenetics in mental illness: hope or hype? , journal = Journal of Psychiatry & Neuroscience , volume = 35 , issue = 6 , pages = 366–8 , date = Nov 2010 , pmid = 20964959 , pmc = 2964366 , doi = 10.1503/jpn.100148 The aim of future research is to reprogram epigenetic changes to help with addiction, mental illness, age related changes, memory decline, and other issues. However, the sheer volume of consortium-based data makes analysis difficult. Most studies also focus on one gene.{{cite book , vauthors = McCaffery JM , chapter = Genetic epidemiology of stress and gene by stress interaction , veditors=Baum A, Contrada RJ , title = The Handbook of Stress Science: Biology, Psychology, and Health , publisher = Springer Publishing Company , location = New York , year = 2010 , pages = 78–85 , isbn = 978-0-8261-1471-6 In actuality, many genes and interactions between them likely contribute to individual differences in personality, behaviour and health.{{cite journal , vauthors = Kalant H , title = What neurobiology cannot tell us about addiction , journal = Addiction , volume = 105 , issue = 5 , pages = 780–9 , date = May 2010 , pmid = 19919596 , doi = 10.1111/j.1360-0443.2009.02739.x 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.{{cite book , vauthors = Guo G , chapter = Family influences on children's well being: potential roles of molecular genetics and epigenetics , veditors=Landale N, Booth A, McHale S , title = Biosocial Foundations of Family Processes (National Symposium on Family Issues) , publisher = Springer , location = Berlin , year = 2010 , pages = 181–204 , isbn = 978-1-4419-7360-3

Limited access to human brain tissue poses a challenge to conducting human research. 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. Although some epigenetic studies have translated findings from animals to humans,{{cite journal , vauthors=McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ , date=Mar 2009 , title=Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse , journal=Nature Neuroscience , volume=12 , issue=3 , pages=342–8 , doi=10.1038/nn.2270 , pmc=2944040 , pmid=19234457 some researchers caution about the extrapolation of animal studies to humans. 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.

Some researchers note that epigenetic perspectives will likely be incorporated into pharmacological treatments. 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. 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. Future research may also focus on epigenetic changes that mediate the impact of psychotherapy on personality and behaviour.

Most epigenetic research is correlational; it merely establishes associations. More experimental research is necessary to help establish causation.{{cite journal , vauthors = Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray RM, Mill J , title = Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder , journal = Human Molecular Genetics , volume = 20 , issue = 24 , pages = 4786–96 , date = Dec 2011 , pmid = 21908516 , pmc = 3221539 , doi = 10.1093/hmg/ddr416 Lack of resources has also limited the number of intergenerational studies. Therefore, advancing longitudinal and multigenerational, experience-dependent studies will be critical to further understanding the role of epigenetics in psychology.

See also

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

References

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Further reading

{{refbegin, 33em
* {{cite journal , vauthors = Lester BM, Tronick E, Nestler E, Abel T, Kosofsky B, Kuzawa CW, Marsit CJ, Maze I, Meaney MJ, Monteggia LM, Reul JM, Skuse DH, Sweatt JD, Wood MA , title = Behavioral epigenetics , journal = Annals of the New York Academy of Sciences , volume = 1226 , issue = 1, pages = 14–33 , date = May 2011 , pmid = 21615751 , doi = 10.1111/j.1749-6632.2011.06037.x , bibcode = 2011NYASA1226...14L , pmc = 3783959
* {{cite journal , vauthors = Champagne FA, Rissman EF , title = Behavioral epigenetics: a new frontier in the study of hormones and behavior , journal = Hormones and Behavior , volume = 59 , issue = 3 , pages = 277–8 , date = Mar 2011 , pmid = 21419246 , doi = 10.1016/j.yhbeh.2011.02.011 , s2cid = 17285061
* {{cite journal , vauthors = Nelson ED, Monteggia LM , title = Epigenetics in the mature mammalian brain: effects on behavior and synaptic transmission , journal = Neurobiology of Learning and Memory , volume = 96 , issue = 1 , pages = 53–60 , date = Jul 2011 , pmid = 21396474 , pmc = 3463371 , doi = 10.1016/j.nlm.2011.02.015
* {{cite journal , vauthors = Plazas-Mayorca MD, Vrana KE , author-link2=Kent Vrana, title = Proteomic investigation of epigenetics in neuropsychiatric disorders: a missing link between genetics and behavior? , journal = Journal of Proteome Research , volume = 10 , issue = 1 , pages = 58–65 , date = Jan 2011 , pmid = 20735116 , pmc = 3017635 , doi = 10.1021/pr100463y
* {{cite journal , vauthors = Curley JP, Jensen CL, Mashoodh R, Champagne FA , title = Social influences on neurobiology and behavior: epigenetic effects during development , journal = Psychoneuroendocrinology , volume = 36 , issue = 3 , pages = 352–71 , date = Apr 2011 , pmid = 20650569 , pmc = 2980807 , doi = 10.1016/j.psyneuen.2010.06.005
* {{cite journal , vauthors = Crews D , title = Epigenetic modifications of brain and behavior: theory and practice , journal = Hormones and Behavior , volume = 59 , issue = 3 , pages = 393–8 , date = Mar 2011 , pmid = 20633562 , pmc = 3401366 , doi = 10.1016/j.yhbeh.2010.07.001
* {{cite journal , vauthors = Mann JJ, Currier DM , title = Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression , journal = European Psychiatry , volume = 25 , issue = 5 , pages = 268–71 , date = Jun 2010 , pmid = 20451357 , pmc = 2896004 , doi = 10.1016/j.eurpsy.2010.01.009
* {{cite journal , vauthors = Crews D , title = Epigenetics, brain, behavior, and the environment , journal = Hormones , volume = 9 , issue = 1 , pages = 41–50 , year = 2010 , pmid = 20363720 , doi = 10.14310/horm.2002.1251 , doi-access = free
* {{cite journal , vauthors = Malvaez M, Barrett RM, Wood MA, Sanchis-Segura C , title = Epigenetic mechanisms underlying extinction of memory and drug-seeking behavior , journal = Mammalian Genome , volume = 20 , issue = 9–10 , pages = 612–23 , year = 2009 , pmid = 19789849 , pmc = 3157916 , doi = 10.1007/s00335-009-9224-3
* {{cite journal , vauthors = Nicolaïdis S , title = Prenatal imprinting of postnatal specific appetites and feeding behavior , journal = Metabolism , volume = 57 , issue = Suppl 2 , pages = S22-6 , date = Oct 2008 , pmid = 18803961 , doi = 10.1016/j.metabol.2008.07.004
* {{cite journal , vauthors = McGowan PO, Meaney MJ, Szyf M , title = Diet and the epigenetic (re)programming of phenotypic differences in behavior , journal = Brain Research , volume = 1237 , pages = 12–24 , date = Oct 2008 , pmid = 18694740 , pmc = 2951010 , doi = 10.1016/j.brainres.2008.07.074
* {{cite journal , vauthors = Szyf M, Weaver I, Meaney M , title = Maternal care, the epigenome and phenotypic differences in behavior , journal = Reproductive Toxicology , volume = 24 , issue = 1 , pages = 9–19 , date = Jul 2007 , pmid = 17561370 , doi = 10.1016/j.reprotox.2007.05.001
* {{cite journal , vauthors = Bonasio R, Zhang G, Ye C, Mutti NS, Fang X, Qin N, Donahue G, Yang P, Li Q, Li C, Zhang P, Huang Z, Berger SL, Reinberg D, Wang J, Liebig J , title = Genomic comparison of the ants Camponotus floridanus and Harpegnathos saltator , journal = Science , volume = 329 , issue = 5995 , pages = 1068–71 , date = Aug 2010 , pmid = 20798317 , doi = 10.1126/science.1192428 , bibcode = 2010Sci...329.1068B , pmc = 3772619
{{refend

External links

{{refbegin
* {{cite web , url = http://www.cbc.ca/video/news/audioplayer.html?clipid=2161607978 , title = The Fingerprints of Poverty , vauthors = McDonald B , year = 2011 , work = Quirks & Quarks , publisher= CBC Radio , quote=Audio interview with Moshe Szyf, a professor of Pharmacology and Therapeutics at McGill University, discusses how epigenetic changes are related to differences in socioeconomic status.
* {{cite web , url = http://www.doctoroz.com/videos/control-your-pregnancy , title = Control Your Pregnancy , vauthors = Oz M , year = 2011 , work = The Dr. Oz Show , quote = Video explaining how epigenetics can affect the unborn fetus.
* {{cite web, url=http://www.scivee.tv/node/20905 , title=Epigenetic Landscapes , vauthors=Paylor B , year=2010 , quote=This video addresses how, in principle, accumulated epigenetic changes may result in personality differences in identical twins. This video was made by a Ph.D. candidate in experimental medicine and award winning filmmaker Ben Paylor. , url-status=dead , archive-url=https://web.archive.org/web/20131215182353/http://www.scivee.tv/node/20905 , archive-date=2013-12-15 page text.
* {{cite magazine , url = http://www.scientificamerican.com/article.cfm?id=epigenetics-explained , title = Epigenetics Explained (Animation) , vauthors = Rusting R , date = November 2011 , magazine = Scientific American , quote = A series of diagrams explaining how epigenetic marks affect genetic expression.
{{refend

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{{Evolutionary psychology

Personality
Epigenetics
Neuroscience
Behavioural genetics