Epigenetics: Stress and mental illness

Describe two studies Abert uses in his paper that considers epigenetic studies in rats and mice.

1. offspring of rat mothers with poor maternal care had the phenotype of an increased stress response/reactivity (increased methylation of the GC promoters, leading to a heightened HPA stress response) 2. persistent DEMYLATION of the VASPRESSIN PROMOTER is associated with early life stress in mice

What are three possible issues with the effort to create "reference" genomes?

1. the large sample size is associated with problems of associative power (variability diagnoses, the "hyper-normal" group which is screened for any past mental disorder, partial methylation. 2. variability in methylation \and variability in the ways in which each specific cell type is methylated (very specific, not helpful as a model). 3. Methylation is not all or nothing- there can be partial methylation

According to McGowan et al, is GC more associated with suicide completion or abuse?

Abuse

Describe epigenetic mechanisms and their importance. Name and define two examples of epigenetic alterations

Acetylation and methylation. Epigenetic mechanisms- allow traits and genes to be expressed differently without changing the DNA at all, and may even span generations. Phenotypic trait variations at cellular and phisiological levels caused by external or environmental factors

What are Extracellular Vesicles?

Appear to be involved in the maturation of sperm, delivered to female reproductive tract during ejaculation and affect the developing embryo. Enclose many different protiends and miRNAs within a membrane vesicle

What are two examples of early life stress in lab animals and do both involve epigenetic changes

BOTH DO. maternal transmission- ex. neonatal handling into subsequent generations. Also, genetic transmission, ex. odor-potentiated startle effects into future generations

What is a histone and what is its purpose? Why is it so important in Epigenetics and gene expression?

DNA wraps around it to be more compact. It is important because histone methylation and modulation decides with genes are available for mRNA to be created and thus which can be expressed and how they are expressed

How can DNA methylation be an epigenetic marker for mental disorders for schizophrenia?

Epigenetic markers may be quantifiable/tangible markers of lifetime stress or heritable predispositions for mental illness. For schizophrenia, a marker could be REDUCED PREPULSE INHIBITION- methylation of reeling gene

List 3 epigenetic differences between Hi LGABN and low PGABN offspring

High: enhanced DNA demethylation, increased histone deacytalation, increased GR expression in hippocampus. Low: enhanced DNA methylation in hippocampus, decreased histone deacytaltion decreased GR expression in hippocampus

what were the principal findings of the McGowan et al study regarding GR expression?

Hippocampal NR3C1 gene expression is decreased in samples from suicide victims with a history of childhood abuse compared with other groups. No difference in GR expression found between suicide victims without childhood abuse and control. The pattern of results for hippocampal expression of the GC receptor of the 1F variant wa identical to that of the total glucocorticoid receptor expression

What is a histone, what two processes modify them, and what happens to DNA that is wrapped around a histone October compared to DNA that is not?

Histones: portends around with DNA can wind for compaction and gene regulation. Modified via methylation or acetylation. DNA that is wrapped around a histone is very compact, and inactive due to its inability to create mRNA. Not wrapped= accessible

How does Albert suggest that we improve our understanding of Epigenetics for use in future research on mental disorders?

Identification of dysregulated gene clusters. Also, greater understanding of FACTORS affecting DNA methylation and their effects on genome-wide methylation petterns in order to help with future ability to treating methylation patterns and mental illness

According to McGoawn et. al, how does ACTH relate to childhood abuse and HPA activity?

Increased ACTH in individuals who had suffered child abuse. Pituitary ACTH directly reflects central activation of the HPA stress response- basically pituitary activity is a measure of HPA activity and the greater stress response

Name 3 effects that HIGH LGABN by mothers had on rat pups

Increased Serotonin turnover in hippocampus Enhanced DNA demethylation Increased Histone Acetylation Increased GR expression in hippocampus heavier adrenal gland?

What are 2 ways in which Albert argues that it is unclear whether epigenetic association studies in mental illness would be more productive?

Large sample sets have problems which detract from their power as associative tools. Also, the term "epigenetic change" is extremely broad and refers to a wide variety of actions. Epigenetic modification can refer to partial or full methylation at many sites, and there are different things per cell- therefore, it is unclear that any sort of study could be a good marker.

List two limitations of epigenomics and their implications for mental illness.

Large sample size is associated with problems which interfere with the power of association (use of hyper-normal controls, screened for any mental illness), varaiblity in diagnosis, partial methylation of some methylation sites, etc Cell and tissue specificity- each specific cell gets methylated and demythateld differently, value of epicnomes is therefore limited for neuronal cells due to their inherent diversity

The effects of removal of rat litters from their mothers for 15 minutes seemed counterintuitive at first. What are these effects, and what is a possible explanation for them?

Levine (first) rats that were handled weighed more at weaning, signifying a heavier adrenal gland and higher stress reactivity. Second: handled animals were more active in the inner squares of the open field on days 2-4, suggesting less emotionality/anxiety. they all had lower levels of plasma corticosterone. Possible explanation: reunion might have increased LB behaviors in the mothers, and so this was a model of maternal separation increasing maternal care

What were the main rodent research findings that informed the McGowan et al study examining epigenetic regulation of the GC receptor in the human hippocampus?

Maternal behaviors altered the development of the HPA response to stress in rats through specific effects on gene transcription, including forebrain GC receptor expression. The activation of GC receptors inhibits the HPA response through negative feedback, there fore the selective knockdown of these receptors is associated with increased HPA activity under all conditions. Therefore, GC over expression is associated with a dampened stress response

What factors did McGowan find affected GC receptor expression? What factors did not affect GC receptor expression? How do these finding compare with previous studies?

No difference in GC receptor expression in suicide victims without a history of abuse and controls, which meant that the GC receptor changes were closely associated with young life stress rather than suicide completion. Earlier studies asserted that early childhood abuse was associated with increased pituitary ACTH responses, regardless of whether they had current depressions. ACTH affects the HPA axis and GC expression dampens stress response. These results agree with the prior studies, which focus on early trauma as a factor in an increased stress response rather than having depression

Describe the weaver et al study on rats and DNA methylation and its connection to mental illness

Offspring of rat mothers that provided poor maternal care grew up to have increased stress reactiity. This was also associated with INCREASED METHYLATION at specific sites of the glucoricoid promoters. Basically , the way their epienetics were was that their GR promoter gene was inhibited through methylation, therefore decreased GC promoter= decreased negateive feedback on HPA, harder to terminate the HPA stress response Reversible early in the rats life but as they got older it became harder to reverse- shows that early environment is crucial for behavioral phenotypes. Also, early childhood trauma was associated with DNA methylation in the analogous site of the GR gene in hippocampus of suicide victims. This shows that DNA methylation is an epigenetic change that could truly alter behavior in humans through environment, and we dont know if this is reversible in humans.

What do McGowan et all findings suggest regarding a potential cause of the transmission of genetic vulnerability for depression from parents to children?

Part of the vulnerability could occur from epigenetic modifications of regions implicated in the stress response

What conclusions did the first Levine study report regarding the effects of neonatal handling on the ability of rat pups to respond to stressors and how did they come to these conclusions?

Rats were either handled (removed from mothers) each day after birth or they were left alone. At 70 days, they injected all of the rats causing a stressor. As a result, the animals weighed significantly more when they had been handled. Higher weights suggests higher adrenal weight and thus greater fight or flight response. Therefore, handled rats were less able to cope with stressors

Please provide a description of how maternal behavior alters the HPA axis stress response.

Studies of rat mothers and offspring have shown that rats with less loving mothers developed the phenotype of greater reactivity to stressors. This was shown by a methylation of the specific site of a GC promoter which promoted GC receptor expression in the hippocampus. The methylation caused less GC receptors, leading to a worsened ability to terminate the HPA stress response. These effects became irreversible as time went on implying that early life stressors continue to have an effect later in life.

Please summarize the methods employed for data collection in the McGowan study

Used hippocampal samples from 12 suicide victims with a history of child abuse, 12 suicide victims with no such history, and 12 controls (died due to accident). Subjects were matched for gender, age, etc. They found out information from structured interviews using the Childhood Experience of Care and Abuse questionnaire adapted for psychological autopsies. They assessed for genetic variation in the NR3C1 promoter region by aligning DNA. They extracted DNA and RNA and did a methylation analysis and other DNA tests to compare DNA and RNA samples

What is Albert's conclusion on epigenetic changes as markers of risk for mental illness?

We don't know enough about them/about mental illness to know for sure if they will be good markers. However, they may lead to production and prescription of more selective/personal mental illness treatments. These studies may also show patterns between behaviors and epigenetic markers. But we don't know if these patterns are useful because of the variety of brain regions and neuronal cell types. It would be helpful to understand the MECHENASIM through which methylation occurs and the factors which affect it to better understand accuracy of treatments for it

Are the findings of McGowan et al consistent with animal studies? Support with one of the studies mentioned

Yes: studies of rodents and primate show that persistent disruptions of mother infant interactions are associated with increased ACTH expression and HPA response to stress (ex the non handled rats weighed more at 2 weeks). Variations in maternal care in the rat influence hippocampal GC receptor expression, as well as methylation of the NR3C1 promoter analog for humans

Define non-genomic transmission and describe the research that led to the term being coined

heritability of traits from biological parents that is not reflected in DNA. One of the first studies: female rats with litters were observed for 10 days, divided mothers into high LGABN groups and low PGABN groups. they cross fostered rats of high mothers and low mothers and vice versa, to determine if the rat behavior was genetically determined or non-genomic transmission. Results showed that the type of care the received DID in fact affect the open field bahavior of the rats, and this actually endured through generations (though it eventually fades out)

Describe the experimental design that demonstrated the transmission of fear across generations. What were the behavioral results?

mice were trained to associate a certain smell with foot shocks (Odor-potentiated startle). they were then mated with females who did not have this reaction. these offspring were then mated with naive females as well. Results: startle response observed in F1 animals whose fathers were trained to associate smell with mild footshock- visible effects in GRANDCHILDREN, who were never paired with shock

How does Albert suggest conducting an intervention for mental illness, based on epigenetic modifications? At what Stage in life should this intervention be done?

modifying DNA methylation and inhibiting histone deacetylation. More selective histone deacetylase inhibitors might be key. This is based on the fact that histone deacetylace inhibitors can reverse the effects of chronic social defeat stress in mice. Also, intervention should be done EARLY life as this is the crucial period

Are epigenetic alterations more likely to be transmitted maternally rather than paternally?

no, equally likely by gender

What should be explored more in epigenomics to provide additional information about mental illness?

the mechanisms that regulate (and the factors under which) DNA methylation occurs and the effects of these mechanisms. Basically, how and why and the mechanism for how DNA methylation occurs, so that we can figure out markers of behavioral of disease phenotypes with correlation to behavior

Are epigenetic alterations more likely to be transmitted maternally rather than paternally?

yes