epigenetics, neuroalterations and mental health Flashcards
lecture outline
- review of early life adversity and hormonal alterations
- review of genomic transcription and translation events
- epigenetics and its relation to Developmental Origins of Health and Disease Hypothesis
- psychopathology and hormonal regulation
for something to be considered stressful, individuals must perceive it as…
aversive
but humans are exposed to different circumstances that aren’t necessarily perceived as stressful BUT that can have DEREGULATORY effects on physiological responses that aim to restore homeostasis
adversity (or exposure to adversities) has been used to…
better capture the DEVELOPMENTAL RISKS involved in unhealthy environments
adversity can be conceived as…
- exposure to harmful/threatening stimuli
- absence of stimulation needed for typical development
dimensional approach to childhood adversity - the dimensions
low to high DEPRIVATION
low to high THREAT
ie. NEGLECT is low threat high deprivation
ie. PHYSICAL ABUSE is high threat low deprivation
Romania’s tragic example of negligence
no money to support family - parents abandoned children
gov created orphanages to house them
employees = instructed to show no affection to babies
ignored their cries until they learned they wouldn’t get them attention
all slept in metal cradles
no loving attention/nurturing
lots of physical abuse
filthy conditions
“you were basically treated like an animal”
The Bucharest Project setup
randomized controlled trial of FOSTER CARE as alternative to institutional rearing for abandoned children
The Bucharest Project measures
changes in ANS and HPA axis measures during 3 tasks
2 social stressors (Trier Social Stress Test) which includes preparation, speech and math portions
nonsocial stressor (frustration task)
The Bucharest Project 3 groups
- deprived care as usual
- high quality foster care intervention
- typically developing Romanian
orphans were assigned to intervention groups
The Bucharest Project - timing of placement and HPA axis reactivity
children placed in appropriate care earlier had an ENHANCED CORTISOL RESPONSE
placement at 24 months
the longer they stayed in foster care, the more blunting of the cortisol response (dysfunctional HPA axis)
The Bucharest Project - earlier age of placement also predicted greater _____ engagement
vagal
The Bucharest Project main finding on timing of placement
patterns among children placed earlier in appropriate care…
more closely resembled those in typically developing children
The Bucharest Project found that those in regular orphanages had 2 things
- generally high levels of cortisol throughout the day
- blunted cortisol response
RSA
respiratory sinus arrythmia
respiratory sinus arrythmia
variation in heart rate that occurs during each breathing cycle
the heart rate increases when breathing in and decreases when breathing out
what’s a MORE ADAPTIVE RSA response?
a more de-synchronous relationship between heartbeat and breathing
if stress response is blunted, heart rate and breathing are more synchronous
which is less adaptive
transcription factor
specific DNA sequences that proteins/hormone complexes bind to
play crucial role in regulating the transcription of the gene
promoter
specific sequence of DNA located upstream of a gene
contains binding sites for transcription factors and RNA polymerase
hormones with genetic effects probably act as…
transcription factors
transcription factor facilitates the enzyme RNA polymerase
which synthesizes the RNA
if you observe an increase in RNA molecules, it means…
there’s an active gene
quantifying mRNA is a way of inferring a gene is active
what enzyme is responsible for synthesizing the RNA molecule from a DNA template?
RNA polymerase
this happens during transcription
where does RNA polymerase bind?
promoter region of a gene
with assistance of transcription factors
begins to synthesize RNA molecule complementary to the DNA template
where does the mature mRNA go?
mature mRNA moves from NUCLEUS to CYTOPLASM
what happens to the mRNA once in the cytoplasm?
translation
translation is carried out by…
ribosomes
which are composed of protein and ribosomal RNA (rRNA)
translation - very basic
translating mRNA into PROTEINS
mRNA molecule binds to a ribosome
process of decoding its sequence to produce a protein begins
usually neurons produce just one…
neurotransmitter type
ie. dopaminergic, cholinergic
epigenetics studies…
how behaviours and the environment can cause changes that affect the WAY YOUR GENES WORK
genetic sequence is UNCHANGED
but the environment PHYSICALLY MODIFIES the functioning of the DNA
this MODIFIES GENE EXPRESSION
epigenetic mechanisms are affected by…
- development (in utero, childhood)
- environmental chemicals
- drugs
- ageing
- diet
- stress exposure
epigenetic changes affect what and don’t affect what?
changes in gene activity/function aren’t associated with any change in the DNA sequence itself
but gene expression is modified
2 most common forms of epigenetic mechanisms
DNA methylation
histone modifications
2 types of histone modifications
- acetylation
- deacetylation
acetylation versus deacetylation
ACETYLATION: unfold DNA
DEACETYLATION: coiling of DNA
histones make DNA more or less…
accessible
the more tightly packed the DNA, the less accessible
the less tightly coiled, the easier to access
histone modification can alter…
how the DNA is folded
acetylation: unfolds it
deacetylation: coils it
DNA methylation
transfer of a methyl group to the 5th carbon in a cytosine nucleobase (C)
transcription factor can’t access the promoter region of the gene - physical barrier
results in lower levels of gene expression
what is needed for DNA methylation to occur?
DNA methylation is catalyzed by a family of DNA methyltransferases (Dnmts)
Dnmts transfer the methyl groups to cytosine base in the DNA strand
which can you measure more precisely? DNA methylation or histone modification?
DNA methylation
because it’s easier to access the promoter region of a specific gene
than it is to mess with the individual histones of a gene
methylation of DNA and histones causes…
nucleosomes to pack tightly together
transcription factors cannot bind to the DNA
and genes cannot be expressed
epigenome
epigenetic alterations can be passed down from parents through the genome
DoHaD
Developmental Origins of Health and Disease Hypothesis
DoHaD proposes that…
environmental exposures during critical periods of prenatal and early postnatal development can influence long term health outcomes
early life exposures may alter developmental PATHWAYS, leading to an increased risk of chronic diseases
DoHad - environmental exposures in early life can alter pathways and lead to…
increased risk of chronic diseases
obesity, diabetes, cardiovascular disorders
later in life
Dutch Famine Birth Cohort Study setup
part of DoHaD
conducted after WW2, it investigated long-term health effects of prenatal famine exposure
Dutch Famine Birth Cohort Study results
findings revealed that individuals exposed to famine during early gestation…
had higher rates of:
a) obesity
b) cardiovascular disease
c) psychiatric affective disorders
what’s wrong with this quote: “the new science of epigenetics reveals how the choices you make can change your genes - and those of your kids”
they don’t change your genes
they change your gene FUNCTIONING/EXPRESSION
gametogenesis
process of forming sperm and eggs cells
what occurs during gametogenesis
broadly, the formation of sperm and egg cells
also EXTENSIVE EPIGENETIC REPROGRAMMING in male and female germ cells
this reprogramming includes ERASURE of numerous DNA methylation marks and histone modifications
what are often erased during gametogenesis? however…
DNA methylation marks
histone modifications
certain parts of the genome escape the reprogramming!
parts of genome that escape reprogramming during gametogenesis
imprinting control regions
they MAINTAIN their PARENTAL METHYLATION PATTERNS
imprinting control regions
part of the genome that aren’t reprogrammed during gametogenesis
histone modifications and DNA methylation from parent remain
imprinting control regions allow for the transmission of…
environmentally induced changes in DNA methylation to subsequent generations
potentially impacts the PHENOTYPE and DISEASE SUSCEPTIBILITY of offspring
agouti mice study is a…
classical study in epigenetics
but this isn’t about neuroscience
agouti mice carry a…
mutation in the agouti gene
results in OVER-EXPRESSION of agouti protein
as a result, agouti mice exhibit traits like OBESITY, HYPERPHAGIA, and ABNORMAL COAT COLOUR
in agouti mutant mice…
the agouti gene is constantly turned “on”
phenotype characteristics of agouti mice
yellow coats
obese
susceptible to heart disease and diabetes
what did the study do with the agouti mice?
gave agouti mice dams DIETARY METHYL SUPPLEMENTATION
extra folic acid, vitamin B, choline, betaine
what did the methyl supplementation in agouti dams do? how?
altered the phenotype of offspring
via increased CpG methylation
offspring show INACTIVATION OF THE PROBLEMATIC GENE
agouti mice: higher DNA methylation levels means…
healthier/normal
more brown coats (phenotype) and healthy outcomes
agouti mice study: variations in the phenotype map on to…
variations in the gene
methylation patterns are associated with deactivation of the agouti gene
what study inaugurated the field of neuroscience epigenetics?
poor versus good maternal care in mice
differences have epigenetic effects on glucocorticoid receptors
maternal care and epigenetics of glucocorticoid receptors
specific types of maternal care evoke changes in:
a) DNA methylation
b) chromatin structure
results in RELAXED HISTONE PROTEINS
and therefore INCREASED GR gene expression
a good thing: you want high amounts of glucocorticoid receptors they are what control negative feedback (efficient stress response)
pathway: maternal care and epigenetics of glucocorticoid receptors
changes in DNA methylation/chromatin structure
>
relaxed histone proteins (less coiled)
>
increased GR gene expression
this is good - need enough GR in order to have efficient stress response
maternal care leads to epigenetic effects of glucocorticoid receptors: is this permanent?
these changes emerged in early life
but could be REVERSED by CROSS-FOSTERING to mothers who displayed low levels of licking/grooming and arched-back nursing
and these changes persisted into adulthood
maternal care and HPA axis
maternal care is important for HPA axis regulation
feedback mechanisms are altered if appropriate nurture is absent
maternal care classical epigenetic study: poor maternal care
LOW LICKING and GROOMING
leads to a methylated promoter
transcription factor struggles to bind to GR gene promoter
impedes glucocorticoid receptor expression
results in:
a) high corticosterone levels
b) high anxiety
c) low licking and grooming
maternal care classical epigenetic study:good maternal care
HIGH LICKING and GROOMING
- serotonin is released
- histone acetylase is activated
- histone demethylation
transcription factor can now bind to promoter of GR gene
GR expression
results in:
a) low corticosterone levels
b) low anxiety
c) high licking and grooming
maternal care epigenetic classical study: net result of these actions…
is a GR gene that’s more readily accepting of the NGF1-A transcription factor
leads to more GRs in the hippocampus of the offspring
maternal care epigenetic classical study: methylation of GR in hippocampus is higher for which group?
poor care group
bad because if you don’t have enough GR, not enough negative feedback to attain an efficient stress response
in humans, childhood abuse alters…
HPA stress response
increases risk of suicide
how can we translate epigenetic findings from animal studies into humans?
examine post-mortem brains
tissue samples from donated brains give direct access to cells, proteins and genes potentially implicated in the disease
Douglas Bell Canada Brain Bank
Douglas Bell Canada Brain Bank
largest brain bank in Canada
coordinates brain donation process
prepares and stores brain specimens
distributes samples to researchers
maternal care classical epigenetic study: good maternal care resulted in an increase of what transcription factor?
NGF1-A
expressed in the hippocampus
leads to more GRs in the hippocampus of the offspring = good stress response (negative feedback)
CONTRASTINGLY, in poor care offspring, methylation of glucocorticoid receptors occurs = poor stress response
what did they examine in the study about epigenetic effects of childhood abuse? how did they get access to this?
epigenetic differences in a neuron-specific GLUCOCORTICOID RECEPTOR (NR3C1) PROMOTER
used postmortem hippocampus
postmortem tissue from what 3 sources? epigenetic effects of childhood abuse study
- suicide victims with history of childhood abuse
- suicide victims with no childhood abuse
- controls
epigenetic effects of childhood abuse study: findings
- decreased levels of glucocorticoid receptor mRNA
- mRNA transcripts bearing the glucocorticoid receptor 1 splice variant
epigenetic effects of childhood abuse study: in those who committed suicide AND who were abused in childhood
INCREASED CYTOSINE METHYLATION OF AN NR3C1 PROMOTER
results in less glucocorticoid receptors and therefore a less effective stress response
only in the suicide + abused group
following major early stress such as child abuse and neglect, there’s low…
low TRANSCRIPTION of functional receptor networks
this impedes negative feedback of HPA axis
results in chronically high levels of circulating cortisol
correlates with increased lifelong risk for physical/mental health disorders (esp anxiety and depression)
what results in chronically high levels of circulating cortisol?
low transcription of functional receptor networks
which impedes negative feedback of HPA axis
what is increased methylation of promoter 1F CpG sites associated with?
- higher vulnerability to co-occurring internalizing symptoms
- higher morning cortisol
what does prenatal stress do to the brain?
alters the STRUCTURE
alters the FUNCTION
brain areas particularly affected by prenatal stress
hippocampus
amygdala
PFC
specific ways in which the brain’s structure and function are affected by prenatal stress
- reduced neurogenesis
- retraction of the dendrites of hippocampal and cortical neurons
- physical expansion of dendrites in amygdala
sex-specific effects: elevated cortisol values during early pregnancy were associated with…
- increased right amygdalar development
- poor emotional development
in GIRLS, but not boys, before puberty
2 things to know about the specificities in the effects of stress
- TIMING matters
- NOT ONLY CORTISOL is involved
a) other alterations play a role in development/function of HPA axis
b) ie. touch is important in HPA axis development
levels of what enzyme sharply reduce immediately after separation of pups and mother?
ornithine decarboxylase
ornithine decarboxylase
levels sharply drop after pup-mother separation
it’s the first enzyme required in the synthesis of polyamides
polyamides
synthesized by the enzyme ornithine decarboxylas
involved in regulation of PROTEIN SYNTHESIS
and hence TISSUE GROWTH
if ornithine decarboxylase reduces…
then there is less synthesis of polyamides
and therefore less protein synthesis
and therefore LESS TISSUE GROWTH
pathway from ornithine decarboxylase to tissue growth
pup-mother contact
>
ornithine decarboxylase
>
polyamide synthesis
>
regulation of protein synthesis
>
tissue growth
rapid decline in ornithine decarboxylase concentrations that result from pup-mother separation cannot be prevented by…
placement of the pups with an ANESTHETIZED MOTHER that continued to lactate
shows that INTERACTION IS NEEDED
what is shown by the fact placing pups with anesthetized (but still lactating) mother doesn’t prevent ornithine decarboxylase decline?
interaction is required
implication: interaction is needed for proper tissue growth
GH, prolactin, thyroid-stimulating hormone, blood concentrations of corticosterone: what happened to their levels after maternal separation?
GH: decreased in pups
prolactin and thyroid-stimulating hormone: didn’t decrease
blood corticosterone: increased
what happened to pups that were brushed in a way that approximated the tongue movements of the dam?
this PREVENTED the reduction in ornithine decarboxylase
what prevented the reduction in ornithine decarboxylase in pups?
brushing them in a way that approximated the tongue movements of the dam
what does GH regulate?
OCD (ornithine decarboxylase) activity in the brain and other tissues
after GH is secreted from anterior pituitary gland, it binds (along with types of somatomedins) to receptors on surface of cells
cells that bind GH are stimulated to grow and divide
what happens after GH is secreted from the anterior pituaitary?
binds to receptors on surface of cells
cells that bind GH are stimulated to grow/divide
physiological mechanisms by which tactile stimuli increase GH secretion from the anterior pituitary
are not yet known
practical applications of findings that tactile stimuli increase GH secretion from anterior pituitary
increasing handling of premature infants
stimulates growth and development
in mice with high maternal licking and grooming…
offspring show adaptive stress responses
and normal growth
