Behavioral epigenetics

Source: Wikipedia, the free encyclopedia.

Behavioral epigenetics is the field of study examining the role of

behaviour,[6] cognition,[2] personality,[7] and mental health.[8][9]

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 can have a marked influence on an organism's behavior.[1]

Background

Main article: Epigenetics

In

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.[15][16]

Examples of mechanisms that produce such changes are

silencer
regions of the DNA.

Modifications of the epigenome do not alter 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".[19][20]

Histone modification changes the way that DNA is packaged into chromosomes. These changes impact how genes are expressed.[21]

Epigenetics has a strong influence on the development of an organism and can alter the expression of individual traits.[11] Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span.[4][22] Because some epigenetic modifications can be passed from one generation to the next,[23] subsequent generations may be affected by the epigenetic changes that took place in the parents.[23]

Discovery

The first documented example of epigenetics affecting behavior was provided by

stress later in life.[4] 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.[1] 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.[1]

Research into epigenetics in psychology

Anxiety and risk-taking

Twin studies
help to reveal epigenetic differences related to various aspects of psychology.

In a small clinical study in humans published in 2008,

CpG islands proximal to the DLX1 gene correlated with the differing behavior.[25] 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.[25]

Stress

The hypothalamic pituitary adrenal axis is involved in the human stress response.

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.[26][27][28]

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

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.[26] 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.[26] Further support comes from experiments with the same setup, using drugs that can increase or decrease methylation.[27] 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.[26]

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.[26] The findings were independent of whether the mothers were being pharmaceutically treated for depression.[26]

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.[29] 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

Main article: 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.[30]

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.[31] 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.[32]

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.[33]

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

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.[35]
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.[36][35] These double-strand breaks allow the genes to be transcribed and then translated into active proteins.

One

memory formation and in long-term neuronal plasticity.[37]

DNMT3A2 is another immediate early gene whose expression in neurons can be induced by sustained synaptic activity.[38] 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.[39] 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.[32]

In another mechanism reviewed in 2022,[34] 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

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.[1][40] 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.[1][41] In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.[42][43]

Psychopathology and mental health

Drug addiction

Further information:
G9a, and H3K9me2 § Addiction
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
Note: colored text contains article links.
Nuclear membrane
Plasma membrane
Cav1.2
DARPP-32
PP2B
CREB
ΔFosB
c-Fos
HDAC1
The image above contains clickable links
This diagram depicts the signaling events in the
nuclear factor kappa B), it induces an addictive state.[48][49]

Environmental and epigenetic influences seem to work together to increase the risk of addiction.[51] For example, environmental stress has been shown to increase the risk of substance abuse.[52] In an attempt to cope with stress, alcohol and drugs can be used as an escape.[53] Once substance abuse commences, however, epigenetic alterations may further exacerbate the biological and behavioural changes associated with addiction.[51]

Even short-term substance abuse can produce long-lasting epigenetic changes in the brain of rodents,[51] via DNA methylation and histone modification.[18] 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[51] (e.g., in the nucleus accumbens[54]). 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.[51] 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.[55] These alterations may be long-term, as is evidenced in smokers who still possess nicotine-related epigenetic changes ten years after cessation.[56] Therefore, epigenetic modifications[51] 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.[57]

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

cerebral volume.[59]

Imprecise DNA repair can leave epigenetic scars

DNA damage is increased in the brain of rodents by administration of the addictive substances cocaine,[60] methamphetamine,[61][62] alcohol[63] and tobacco smoke.[64] When such DNA damages are repaired, imprecise DNA repair may lead to persistent alterations such as methylation of DNA or the acetylation or methylation of histones at the sites of repair.[65] These alterations may be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in addiction.

Eating disorders and obesity

Further information:
ΔFosB

Epigenetic changes may help to facilitate the development and maintenance of

anxiety disorders. These anxiety issues can precipitate the onset of eating disorders and obesity, and persist even after recovery from the eating disorders.[66]

Epigenetic differences accumulating over the life-span may account for the incongruent differences in eating disorders observed in monozygotic twins. At

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]. Overall, epigenetics contribute to persistent, unregulated self-control behaviours related to the urge to binge.[22]

Schizophrenia

Further information: Epigenetics of schizophrenia

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

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.[68]

Population studies have established a strong association linking schizophrenia in children born to older fathers.

psychotic disorders like schizophrenia via epigenetics.[70]

Bipolar disorder

Evidence for

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.[73] However, a second study found no epigenetic differences in post-mortem brains from bipolar individuals.[74]

Major depressive disorder

The causes of major depressive disorder (MDD) are poorly understood from a neuroscience perspective.[75] 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.[76]

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.[77][78] Studies in various rodent models of depression, often involving induction of stress, have found direct epigenetic modulation of BDNF as well.[79]

Psychopathy

Epigenetics may be relevant to aspects of psychopathic behaviour through methylation and histone modification.[80] These processes are heritable but can also be influenced by environmental factors such as smoking and abuse.[81] Epigenetics may be one of the mechanisms through which the environment can impact the expression of the genome.[82] Studies have also linked methylation of genes associated with nicotine and alcohol dependence in women, ADHD, and drug abuse.[83][84][85] 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.[86]

Suicide

A study of the brains of 24 who died by suicide, 12 of whom had a history of child abuse and 12 who did not, found decreased levels of glucocorticoid receptor in victims of child abuse and associated epigenetic changes.[87]

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.[88] Knocking down the DNMT3 in the larvae changed the worker to queen-like phenotype.[89] 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.[90]

Limitations and future direction

Many researchers contribute information to the Human Epigenome Consortium.[91] 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.[92] In actuality, many genes and interactions between them likely contribute to individual differences in personality, behaviour and health.[93] 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.[94]

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.[91] Although some epigenetic studies have translated findings from animals to humans,[87] a 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.[93]

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.[91] Future research may also focus on epigenetic changes that mediate the impact of psychotherapy on personality and behaviour.[26]

Most epigenetic research is correlational; it merely establishes associations. More experimental research is necessary to help establish causation.[95] Lack of resources has also limited the number of intergenerational studies.[2] Therefore, advancing longitudinal[94] and multigenerational, experience-dependent studies will be critical to further understanding the role of epigenetics in psychology.[5]

See also

References

  1. ^
    PMID 20595592
    .
  2. ^
    doi:10.1525/bio.2011.61.8.4
    .
  3. ISBN 978-0-13-255770-2
    .
  4. ^
    ISBN 978-0-19-992234-5
    .
  5. ^
    S2CID 18672157
    .
  6. PMID 19958180
    .
  7. PMID 20643310
    .
  8. ^
    S2CID 36721906
    .
  9. PMID 18319075
    .
  10. doi:10.1186/s41935-018-0042-1
    .
  11. ^
    S2CID 40236421
    .
  12. S2CID 28991168
    .
  13. PMID 20975758
    .
  14. PMID 21395852
    .
  15. S2CID 4357965
    .
  16. ^ "Overview of the Roadmap Epigenomics Project". Archived from the original on 2019-11-21. Retrieved 2013-12-15.
  17. PMID 18940229
    .
  18. ^
    PMID 21272014
    .
  19. S2CID 11794102
    .
  20. PMID 15709936
    .
  21. ^ "Histone modifications | Abcam". www.abcam.com. Retrieved 2021-10-09.
  22. ^
    S2CID 24599095
    .
  23. ^
    PMID 9618446
    .
  24. S2CID 1649281
    .
  25. ^
    S2CID 32776461
    .
  26. ^
    S2CID 35879739
    .
  27. ^
    S2CID 18739871
    .
  28. PMID 23336536
    .
  29. ^ Schechter DS, Moser DA, Giacobino A, Stenz L, Gex-Fabry M, Adouan W, Cordero MI, Suardi F, Manini A, Sancho-Rossignol A, Merminod G, Aue T, Ansermet F, Dayer AG, Rusconi-Serpa S. (epub May 29, 2015) Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure. Frontiers in Psychology. http://journal.frontiersin.org/article/10.3389/fpsyg.2015.00690/abstract
  30. PMID 20975755
    .
  31. PMID 25475090
    .
  32. ^
    PMID 27634149
    .
  33. PMID 28620075
    .
  34. ^
    PMID 35098021
    .
  35. ^
    PMID 34197463
    .
  36. PMID 26052046
    .
  37. ^
    PMID 31467272
    .
  38. S2CID 10590208
    .
  39. PMID 28513272
    .
  40. S2CID 36395789
    .
  41. PMID 20219993
    .
  42. PMID 22388814
    .
  43. S2CID 7370920
    .
  44. ^
    PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  45. PMID 22200950
    . Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
  46. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
  47. PMID 24939695
    .
  48. ^
    PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  49. ^
    PMID 23430970
    . The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
  50. PMID 18640924
    . Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
  51. ^
    PMID 21205049
    .
  52. PMID 18938197
    .
  53. ISBN 978-0-8261-1471-6
    .
  54. PMID 18635399
    .
  55. PMID 21863600
    .
  56. PMID 19956754
    .
  57. PMID 3278676
    .
  58. S2CID 10692616
    .
  59. PMID 16458479
    .
  60. S2CID 20849951
    .
  61. S2CID 24182756
    .
  62. PMID 18797138
    .
  63. PMID 18482162
    .
  64. S2CID 9167990
    .
  65. PMID 27259203
    .
  66. PMID 18213688
    .
  67. ISBN 978-1-84882-643-4
    .
  68. ^
    S2CID 16397510
    .
  69. PMID 11296097
    .
  70. ^
    PMID 19783603
    .
  71. PMID 18195365
    .
  72. PMID 19568875
    .
  73. PMID 16984965
    .
  74. PMID 16483362
    .
  75. PMID 22826347
    .
  76. S2CID 13308611
    .
  77. S2CID 21547891
    .
  78. PMID 22922121
    .
  79. PMID 22529779
    .
  80. PMID 19005036
    .
  81. PMID 19777560
    .
  82. PMID 17987668
    .
  83. PMID 18454435
    .
  84. PMID 20875476
    .
  85. PMID 18492038
    .
  86. PMID 20422643
    .
  87. ^
    PMID 19234457
    .
  88. PMID 22983211
    .
  89. S2CID 955740
    .
  90. PMID 23852726
    .
  91. ^
    PMID 20964959
    .
  92. ISBN 978-0-8261-1471-6
    .
  93. ^
    PMID 19919596
    .
  94. ^
    ISBN 978-1-4419-7360-3
    .
  95. PMID 21908516
    .
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Further reading

External links

  • McDonald B (2011). "The Fingerprints of Poverty". Quirks & Quarks. CBC Radio. 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.
  • Oz M (2011). "Control Your Pregnancy". The Dr. Oz Show. Video explaining how epigenetics can affect the unborn fetus.
  • Paylor B (2010). "Epigenetic Landscapes". Archived from the original on 2013-12-15. 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. page text.
  • Rusting R (November 2011). "Epigenetics Explained (Animation)". Scientific American. A series of diagrams explaining how epigenetic marks affect genetic expression.
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