epigenetics, neuroalterations and mental health Flashcards
1
Q
lecture outline
A
- 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
2
Q
for something to be considered stressful, individuals must perceive it as…
A
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
3
Q
adversity (or exposure to adversities) has been used to…
A
better capture the DEVELOPMENTAL RISKS involved in unhealthy environments
4
Q
adversity can be conceived as…
A
- exposure to harmful/threatening stimuli
- absence of stimulation needed for typical development
5
Q
dimensional approach to childhood adversity - the dimensions
A
low to high DEPRIVATION
low to high THREAT
ie. NEGLECT is low threat high deprivation
ie. PHYSICAL ABUSE is high threat low deprivation
6
Q
Romania’s tragic example of negligence
A
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”
7
Q
The Bucharest Project setup
A
randomized controlled trial of FOSTER CARE as alternative to institutional rearing for abandoned children
8
Q
The Bucharest Project measures
A
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)
9
Q
The Bucharest Project 3 groups
A
- deprived care as usual
- high quality foster care intervention
- typically developing Romanian
orphans were assigned to intervention groups
10
Q
The Bucharest Project - timing of placement and HPA axis reactivity
A
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)
11
Q
The Bucharest Project - earlier age of placement also predicted greater _____ engagement
A
vagal
12
Q
The Bucharest Project main finding on timing of placement
A
patterns among children placed earlier in appropriate care…
more closely resembled those in typically developing children
13
Q
The Bucharest Project found that those in regular orphanages had 2 things
A
- generally high levels of cortisol throughout the day
- blunted cortisol response
14
Q
RSA
A
respiratory sinus arrythmia
15
Q
respiratory sinus arrythmia
A
variation in heart rate that occurs during each breathing cycle
the heart rate increases when breathing in and decreases when breathing out
16
Q
what’s a MORE ADAPTIVE RSA response?
A
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
17
Q
transcription factor
A
specific DNA sequences that proteins/hormone complexes bind to
play crucial role in regulating the transcription of the gene
18
Q
promoter
A
specific sequence of DNA located upstream of a gene
contains binding sites for transcription factors and RNA polymerase
19
Q
hormones with genetic effects probably act as…
A
transcription factors
transcription factor facilitates the enzyme RNA polymerase
which synthesizes the RNA
20
Q
if you observe an increase in RNA molecules, it means…
A
there’s an active gene
quantifying mRNA is a way of inferring a gene is active
21
Q
what enzyme is responsible for synthesizing the RNA molecule from a DNA template?
A
RNA polymerase
this happens during transcription
22
Q
where does RNA polymerase bind?
A
promoter region of a gene
with assistance of transcription factors
begins to synthesize RNA molecule complementary to the DNA template
23
Q
where does the mature mRNA go?
A
mature mRNA moves from NUCLEUS to CYTOPLASM
24
Q
what happens to the mRNA once in the cytoplasm?
A
translation
25
translation is carried out by...
ribosomes
which are composed of protein and ribosomal RNA (rRNA)
26
translation - very basic
translating mRNA into PROTEINS
mRNA molecule binds to a ribosome
process of decoding its sequence to produce a protein begins
27
usually neurons produce just one...
neurotransmitter type
ie. dopaminergic, cholinergic
28
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
29
epigenetic mechanisms are affected by...
1. development (in utero, childhood)
2. environmental chemicals
3. drugs
4. ageing
5. diet
6. stress exposure
30
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
31
2 most common forms of epigenetic mechanisms
DNA methylation
histone modifications
32
2 types of histone modifications
1. acetylation
2. deacetylation
33
acetylation versus deacetylation
ACETYLATION: unfold DNA
DEACETYLATION: coiling of DNA
34
histones make DNA more or less...
accessible
the more tightly packed the DNA, the less accessible
the less tightly coiled, the easier to access
35
histone modification can alter...
how the DNA is folded
acetylation: unfolds it
deacetylation: coils it
36
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
37
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
38
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
39
methylation of DNA and histones causes...
nucleosomes to pack tightly together
transcription factors cannot bind to the DNA
and genes cannot be expressed
40
epigenome
epigenetic alterations can be passed down from parents through the genome
41
DoHaD
Developmental Origins of Health and Disease Hypothesis
42
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
43
DoHad - environmental exposures in early life can alter pathways and lead to...
increased risk of chronic diseases
obesity, diabetes, cardiovascular disorders
later in life
44
Dutch Famine Birth Cohort Study setup
part of DoHaD
conducted after WW2, it investigated long-term health effects of prenatal famine exposure
45
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
46
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
47
gametogenesis
process of forming sperm and eggs cells
48
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
49
what are often erased during gametogenesis? however...
DNA methylation marks
histone modifications
certain parts of the genome escape the reprogramming!
50
parts of genome that escape reprogramming during gametogenesis
imprinting control regions
they MAINTAIN their PARENTAL METHYLATION PATTERNS
51
imprinting control regions
part of the genome that aren't reprogrammed during gametogenesis
histone modifications and DNA methylation from parent remain
52
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
53
agouti mice study is a...
classical study in epigenetics
but this isn't about neuroscience
54
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
55
in agouti mutant mice...
the agouti gene is constantly turned "on"
56
phenotype characteristics of agouti mice
yellow coats
obese
susceptible to heart disease and diabetes
57
what did the study do with the agouti mice?
gave agouti mice dams DIETARY METHYL SUPPLEMENTATION
extra folic acid, vitamin B, choline, betaine
58
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
59
agouti mice: higher DNA methylation levels means...
healthier/normal
more brown coats (phenotype) and healthy outcomes
60
agouti mice study: variations in the phenotype map on to...
variations in the gene
methylation patterns are associated with deactivation of the agouti gene
61
what study inaugurated the field of neuroscience epigenetics?
poor versus good maternal care in mice
differences have epigenetic effects on glucocorticoid receptors
62
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)
63
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
64
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
65
maternal care and HPA axis
maternal care is important for HPA axis regulation
feedback mechanisms are altered if appropriate nurture is absent
66
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
67
maternal care classical epigenetic study:good maternal care
HIGH LICKING and GROOMING
1. serotonin is released
2. histone acetylase is activated
3. 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
68
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
69
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
70
in humans, childhood abuse alters...
HPA stress response
increases risk of suicide
71
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
72
Douglas Bell Canada Brain Bank
largest brain bank in Canada
coordinates brain donation process
prepares and stores brain specimens
distributes samples to researchers
73
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
74
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
75
postmortem tissue from what 3 sources? epigenetic effects of childhood abuse study
1. suicide victims with history of childhood abuse
2. suicide victims with no childhood abuse
3. controls
76
epigenetic effects of childhood abuse study: findings
1. decreased levels of glucocorticoid receptor mRNA
2. mRNA transcripts bearing the glucocorticoid receptor 1 splice variant
77
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
78
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)
79
what results in chronically high levels of circulating cortisol?
low transcription of functional receptor networks
which impedes negative feedback of HPA axis
80
what is increased methylation of promoter 1F CpG sites associated with?
1. higher vulnerability to co-occurring internalizing symptoms
2. higher morning cortisol
81
what does prenatal stress do to the brain?
alters the STRUCTURE
alters the FUNCTION
82
brain areas particularly affected by prenatal stress
hippocampus
amygdala
PFC
83
specific ways in which the brain's structure and function are affected by prenatal stress
1. reduced neurogenesis
2. retraction of the dendrites of hippocampal and cortical neurons
3. physical expansion of dendrites in amygdala
84
sex-specific effects: elevated cortisol values during early pregnancy were associated with...
1. increased right amygdalar development
2. poor emotional development
in GIRLS, but not boys, before puberty
85
2 things to know about the specificities in the effects of stress
1. TIMING matters
2. 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
86
levels of what enzyme sharply reduce immediately after separation of pups and mother?
ornithine decarboxylase
87
ornithine decarboxylase
levels sharply drop after pup-mother separation
it's the first enzyme required in the synthesis of polyamides
88
polyamides
synthesized by the enzyme ornithine decarboxylas
involved in regulation of PROTEIN SYNTHESIS
and hence TISSUE GROWTH
89
if ornithine decarboxylase reduces...
then there is less synthesis of polyamides
and therefore less protein synthesis
and therefore LESS TISSUE GROWTH
90
pathway from ornithine decarboxylase to tissue growth
pup-mother contact
>
ornithine decarboxylase
>
polyamide synthesis
>
regulation of protein synthesis
>
tissue growth
91
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
92
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
93
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
94
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
95
what prevented the reduction in ornithine decarboxylase in pups?
brushing them in a way that approximated the tongue movements of the dam
96
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
97
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
98
physiological mechanisms by which tactile stimuli increase GH secretion from the anterior pituitary
are not yet known
99
practical applications of findings that tactile stimuli increase GH secretion from anterior pituitary
increasing handling of premature infants
stimulates growth and development
100
in mice with high maternal licking and grooming...
offspring show adaptive stress responses
and normal growth
101
Harlow surrogate mother experiment
Rhesus monkey infants were provided with two surrogate mothers
one was made of a wire frame, had a nipple protruding from midsection and gave milk to infant
the other provided no nutrition but her wire frame was covered with a soft material to which infant could obtain contact comfort
in presence of strange toy, infants RELY ON THE COMFORT MOM
102
T/F: young humans require tactile stimulation provided by physical contact with caregiver for normal somatic growth/development
true
ie. psychosocial dwarfism
103
psychosocial dwarfism
relatively rare syndrome
found among human infants reared in situations in which they experience little/no physical contact
many disruptions
104
effects of psychosocial dwarfism
1. compromised GROWTH and DEVELOPMENT
a) despite adequate nutrition
2. disruptions of normal SLEEP CYCLES
3. disruption of GH SECRETION
4. absence of TISSUE RESPONSIVENESS to exogenous GH
105
what distinguishes psychosocial dwarfism from hypopituitary dwarfism?
psychosocial dwarfism: no tissue responsiveness to exogenous GH
hypopituitary dwarfism: treatment with GH restores normal growth
106
girl with psychosocial dwarfism example
1. admitted to hospital at 15.3 years
a) height was normal for a 9 year old
b) had abnormal GH release
c) LH and FSH were undetectable
2. after 1 month in hospital
a) began to undergo puberty
3. age 16, living in foster care
a) significant GH release
4. growth continued
a) at 16.9 years, she had grown 27.5 cm
107
attachment styles define degree to which there is...
1. security
2. emotional availability
in the relationship
108
children with SECURE attachment in the Strange Situation
relaxed and mutually enjoyable interaction between the dyad
109
children with INSECURE attachment in the Strange Situation
physical and affective avoidance towards parent
or short verbal exchanges void of affection
110
attachment style and cortisol
SECURE attachment: more adaptive cortisol response
a) less cortisol is released
INSECURE attachment: dysregulation of HPA axis
a) higher response to stress/higher cortisol)
111
how can the HPA axis response of poor toddlers be buffered?
by having ATTACHMENT SECURITY
attachment security buffers the HPA axis of toddlers growing up in poverty
context: when they're receiving inoculations
securely attached children show less cortisol secretion after inoculations
112
effects of an attachment-based intervention on the cortisol production of infants and toddlers in foster care
attachment interventions help with cortisol response/HPA axis
113
attachment security moderates the link between adverse childhood experiences and cellular aging
attachment state and adverse experiences interacted in PREDICTING TELOMERE LENGTH
1. association between number of ACE and telomere length was nonsignificant for secure individuals
2. but was strongly NEGATIVELY ASSOCIATED with ADVERSE EXPERIENCES
114
attachment and aging
securely attached kids show LESS AGING
lower telomere length for insecurely attached kids
115
seems like ______ ______ are responsible for the differences we observe in female and male rat stress response
ovarian hormones
116
female rodents have _______ basal concentrations of corticosterone
greater
117
in response to physical/psychological stressors, female rodents secrete...
higher concentration of corticosterone
118
why is impairment of HPA function more marked in female than male rats?
because female have:
1. greater basal levels of corticosterone
2. higher concentrations of corticosterone in response to physical/physiological stress
119
what about the adrenal gland is different between males and females?
LARGER in females than in males
and the adrenal gland produces glucocorticoids
120
is there a difference in the size of the stress response between males and females?
yes
females have an increased response to fear and stress
121
is there a sex difference in cortisol secretion in response to stress?
yes
males secrete less cortisol in response to stress
122
are sex differences in stress response ACTIVATED or ORGANIZED by hormones?
seems like they're ACTIVATED by hormones
ie. ovariectomy in adulthood eliminates the sex difference in the HPA axis response, and estradiol replacement therapy restores it
123
ovariectomy in adulthood eliminates the sex difference in the HPA axis response, and estradiol replacement therapy restores it: what 2 important things does this tell us?
1. sex differences in stress response are ACTIVATED rather than organized by hormones
2. seems like ovarian hormones are responsible for the differences we observe in female and male rat stress response
124
how do societal gender roles affect stress sex differences?
societal gender roles often result in woman FACING MORE STRESSORS than men
125
men and women tend to respond more to different types of stress
MEN: stressors involving ACHIEVEMENT pressure
WOMEN: may find INTERPERSONAL CONFLICT more stressful
126
does stress affect the sexes equally in terms of COGNITIVE FUNCTION and ATTENTION?
no
affects MEN more
127
emotional and addictive eating is more prevalent...
in females
128
are men or women more likely to experience childhood trauma?
women are
women also suffer higher levels of childhood stress
129
what does stress do to testosterone production?
INHIBITS it
and low testosterone levels reduce both SEXUAL MOTIVATION and PERFORMANCE
(an effect of stress on reproductive function in males)
130
in males, the release of CRH and endogenous opioids can directly suppress what?
the release of GnRH
(an effect of stress on reproductive function in males)
131
in males, the activation of CRH receptors in ACTH-releasing cells stimulates what?
protein kinase A pathway
this leads to CHANGES IN GENE TRANSCRIPTION and other cellular functions
(an effect of stress on reproductive function in males)
132
have CRH and its receptors been identified in the testes and ovaries?
yes
this suggests that this releasing hormone may also DIRECTLY INHIBIT STEROID PRODUCTION
(an effect of stress on reproductive function in males)
133
the fact that CRH and its receptors have been identified in the testes and ovaries suggests that...
this releasing hormone (CRH - cortico-releasing hormone) may also directly inhibit steroid production
134
what can both CRH and VASOPRESSIN stimulate?
the expression of the genes for proopiomelanocortin (POMC) in the anterior pituitary
POMC can be processed by various enzymes to yield several peptides, including ACTH and beta-endorphin
both endogenous and exogenous opioids inhibit secretion of GnRH and LH
135
PMC can yield what?
(recall: CRH can lead to expression of POMC)
POMC can be processed by various enzymes to yield several peptides...
including ACTH and beta-endorphins
AND both endogenous and exogenous opioids inhibit secretion of GnRH and LH
136
both endogenous and exogenous opioids inhibit secretion of what?
GnRH and LH
basically, CRH stimulates expression of POMC genes. POMC can yield ACTH and beta-endorphins. and endogenous and exogenous opioids inhibit GnRH and LH secretion
(an effect of stress on reproductive function in males)
137
plasma LH concentrations are _______ after endorphin treatment
reduced
reduction in LH caused by endorphin is REVERSED by treatment with opioid antagonist naloxone
138
glucocorticoids can inhibit male reproduction in ______ ways
several
139
at high concentrations, what do glucocorticoids suppress?
GnRH and LH secretion
impacts reproduction
140
glucocorticoids effects on protein formations - reproduction
glucocorticoids have been reported to INHIBIT the formation of proteins needed for production of:
a) hormone receptors
b) steroidogenic enzymes
c) intracellular signalling molecules
141
how does cortisol inhibit testosterone secretion in men?
by acting on TESTICULAR LH RECEPTORS
cross-reaction!
142
Leydig cells do what?
produce testosterone
143
stress and male reproduction: leydig cells have GRs that...
are involved in normal processes of CELL GROWTH, METABOLISM, ENERGY USE
but when glucocorticoids are elevated for a long time (esp in subordinate animals)...
an enzyme that normally neutralizes glucocorticoids at basal concentrations is overwhelmed and testosterone production is curtailed
144
stress and male reproduction: leydig cells - when glucocorticoids are elevated for a long time - what happens?
TESTOSTERONE PRODUCTION IS CURTAILED
leydig cells contain GRs that are involved in cell growth, metabolism and energy use
but when glucocorticoids are high for a long time
an ENZYME THAT NORMALLY NEUTRALISES GLUCOCORITOIDS AT BASAL CONCENTRATIONS IS OVERHWELMED
testosterone production is curtailed
145
what do glucocorticoids do to spermatogenesis?
suppress it
146
do glucocorticoids suppress spermatogenesis more directly through a) acting on testosterone levels or b) acting on Leydig cells
through ACTING ON TESTOSTERONE LEVELS
because the effects on Leydig cells just indirectly lower testosterone
147
glucocorticoids suppress spermatogenesis through acting on testosterone levels. this resulting low testosterone may fail to...
support spermatogenesis
such that SPERM COUNTS FALL
and stressed individuals become INFERTILE
148
does social status affect infertility?
social status appears to affect TESTICULAR ENZYMES
these enzymes in turn MEDIATE ANDROGEN PRODUCTION and FERTILITY
149
dominant rats have higher levels of the enzyme that...
counteracts elevated glucocorticoid concentrations
ENSURES FERTILITY
dominant rats are more able to cope with stressors
150
what does a moderate amount of activity/exercise do to testosterone levels?
raises testosterone concentrations
151
what does mild exercise do to neurogenesis?
promotes neurogenesis in the hippocampus
this counteracts the effects of stress
152
exercise counteracts the effects of stress through what?
through promoting neurogenesis in the hippocampus
153
excessive exercise can be interpreted the body as...
stress
can cause sustained glucocorticoid secretion
this leads to low testosterone concentrations
154
running a marathon...
is associated with higher glucocorticoid secretion
155
most common effects of stress on human copulation typically involve...
EPINEPHRINE and SYMPATHETIC SIGNALS
stress and erectile disfunction
156
to generate a penile erection, both sympathetic and parasympathetic NS must...
ACT TOGETHER
in opposition
157
how do the sympathetic and parasympathetic NS work in opposition to generate a penile erection?
1. ERECTION INITIATION: parasympathetic nervous system must be activated
2. as copulation proceeds, the rest of the body maintains high sympathetic tone (the sympathetic NS increases heart rate and BP)
3. genitalia retains its parasympathetic tone UNTIL SUFFICIENT STIMULATION occurs, then parasympathetic input SUDDENLY ENDS
4. simultaneously, sympathetic inputs to the penis are activated and EJACULATION OCCURS
158
what system is activated for erection initiation?
parasympathetic NS in the genitalia
159
erection: as copulation proceeds, rest of body maintains...
high sympathetic tone
which increases heart rate and BP
160
erection: genitalia retains its parasympathetic tone until...
sufficient stimulation occurs
then parasympathetic input suddenly ends
161
erection: parasympathetic input suddenly ends and simultaneously...
sympathetic inputs to the penis are activated and ejaculation occurs!
162
during stress, what happens to erections? why?
harder to get an erection
becomes increasingly difficult to establish parasympathetic activity in the penis
because of the stress-induced high sympathetic input
163
successful ovulation and onset of mating behaviour in females can be disrupted by what?
stress
164
what does successful ovulation and onset of mating behaviour in females depend on?
precise timing of neuroendocrine events
165
stress effects on reproductive function in females
stress can interrupt ESTROUS cycles
stress can cease the MENSTRUAL cycle
166
stress effects on female reproductive function: women with FUNCTIONAL HYPOTHALAMIC AMENORRHEA display...
elevated cortisol concentrations
(functional hypothalamic amenorrhea: no menstrual cycles and no pulsatile release of GnRH from hypothalamus)
167
mammals have _______ to inhibit _______ when they fall into a negative energy balance
MECHANISMS to inhibit REPRODUCTION
women who DIET RIGOROUSLY or EXERCISE STRENUOUSLY often have FERTILITY PROBLEMS
168
in long distance runners, LH pulses...
are less frequent
169
treatment of well-fed female hamsters with a molecule that PREVENTS GLUCOSE UTILIZATION...
SUSPENDS ESTROUS CYCLES
thus, stress appears to interrupt estrous cycles by affecting METABOLIC PATHWAYS
170
hamster study shows that stress interrupts estrous cycles by...
affecting metabolic pathways
171
glucocorticoids at high concentrations can suppress secretion of...
GnRH and LH
in males and females
172
hyperandrogenism
can be caused by stress in females
173
signs of hyperandrogenism
1. male pattern balding
2. virilization
3. acne
4. abnormal hair growth
174
overactive adrenal cortices
one additional mechanism of REPRODUCTIVE IMPAIRMENT in females
remember that adrenal glands secrete androgens in both males and females
small amounts of ANDROSTENEDIONE hormone can interrupt female reproductive processes
1. many of these androgens = converted too estrogens in fat cells
during food shortages, less estrogen is produced in fat cells
contributes to LOW CIRCULATING ESTROGEN
2. more importantly, increased androgen concentrations disturbs negative feedback mechanism of GnRH and gonadotropins
175
small amounts of ANDROSTENEDIONE hormone can...
interrupt female reproductive processes
caused by overactive adrenal cortices (which produce androgens)
176
overactive adrenal cortices and androgens: 2 effects
1. androgens are increased - many of these androgens are CONVERTED TO ESTROGEN in fat cells
a) during food storage less estrogen is produced in fat calls - contributes to LOW CIRCULATING ESTROGEN
2. more importantly, increased androgen concentrations DISTURBS NEGATIVE FEEDBACK mechanisms of GnRH and gonadotropins
CAUSES REPRODUCTIVE IMPAIRMENT IN FEMALES
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stress hormones influence the brain how?
influence STRUCTURE
influence FUNCTION
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stress hormones like cortisol influence the brain where?
key areas for LEARNING
amygdala, hippocampus, PFC (all part of brain's LIMBIC SYSTEM)
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brain system particularly influenced by cortisol
limbic system
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stress causes the amygdala, hippocampus and PFC to be...
1. on HIGH ALERT for danger
2. QUICK to REACT
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stress changes amygdala, hippocampus, PFC - which affect individual's ability to...
1. regulate EMOTION
2. regulate ATTENTION
3. regulate BEHAVIOUR
4. LEARN
5. REMEMBER
^ these are all key components of academic success and health outcomes
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cortisol's effects on the PFC
generally: reductions
1. structural changes
a) fewer and altered connections
2. functional changes
a) difficulty regulating thoughts
b) difficulty regulating emotions
c) difficulty regulating behaviour
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brain areas that help shut off the stress response
PFC
Hippocampus
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brain areas that turn on stress hormones and increase heart rate
amygdala
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cortisol's effect on the hippocampus
1. structural changes
a) fewer connections
b) fewer new neurons created
c) smaller volume
2. functional changes
a) memory difficulties
b) difficulty contextualizing new situations/info
c) difficulty storing new learning
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cortisol's effect on the amygdala
1. structural changes
a) altered connections
b) increased volume
2. functional changes
a) hyperractive stress response
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stress and the brain youtube video
1. chronic stress affects brain SIZE, STRUCTURE, FUNCTION - down to the GENES
2. HPA axis is the basis of all this - it's instantly activated with stress
3. high cortisol over time wreaks havoc on the brain
4. high cortisol increases activity in the amygdala (fear centre)
5. high cortisol causes hippocampus function to deteriorate (learning, memory, stress control)
6. hypothalamus is also affected negatively
7. PFC shrinks, loss of synapses, less neurogenesis in hippocampus
8. ^ results in struggling to learn/remember things, higher depression and Alzheimer's risk
9. goes down to DNA - modulates cortisol receptors which stick to cortisol and dampen the stress response (negative feedback is impeded)
10. effects which genes are EXPRESSED as opposed to the actual gene (epigenetic)
11. passed down generations
12. but you can reverse the ways that cortisol changes your brain (through EXERCISE and NUTRITION)
13. exercise and nutrition INCREASE HIPPOCAMPUS SIZE (improves memory and stress response)
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how can you reverse the ways that cortisol changes your brain?
exercise and meditation
these both INCREASE HIPPOCAMPUS SIZE
and improve memory and stress response
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when do mood disorders typically emerge?
during adolescence
when HORMONE CONCENTRATIONS ARE CHANGING dramatically
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adolescence and mood disorders - hormone concentrations are changing dramatically...
the interactions of these hormones with STILL-MATURING BRAINS can trigger...
DYSFUNCTIONAL AFFECTIVE RESPONSES in susceptible individuals
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susceptible individuals to mood disorders
have some combo of GENETIC and ENVIRONMENTAL pressures for disordered moods
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sex differences in mood disorders
sex diffs begin at PUBERTY
generally women are at TWICE THE RISK compared with men
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examples of affective disorders
depression
bipolar
perimenstrual syndrome
seasonal affective disorder
postpartum depression
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mood disorders are classified on a _________
spectrum/continuum
from DEPRESSION to MANIA
depression > melancholia > normal > hypomania > mania
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DSM criteria for major depressive disorder
must experience 5 or more of a list symptoms during the same 2-week period
and at least one of the symptoms should be either 1) depressed mood or 2) loss of interest or pleasure
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MDD: DSM says that at least one of the symptoms should be either...
1) depressed mood
2) loss of interest or pleasure
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MDD list of symptoms
(must experience 5+ of these symptoms during same 2-week period)
1. DEPRESSED MOOD most of the day, nearly every day
2. markedly DIMINISHED INTEREST/PLEASURE in all or almost all activities most of the day, nearly everyday
3. significant WEIGHT LOSS when not dieting, WEIGHT GAIN or decrease/increase in APPETITE nearly every day
4. INSOMNIA or HYPERSOMNIA nearly everyday
5. PSYCHOMOTOR AGITATION or RETARDATION nearly everyday
6. FATIGUE or loss of energy nearly everyday
7. feelings of WORTHLESSNESS or excessive/inappropriate GUILT nearly everyday
8. diminished ability to THINK/CONCENTRATE, INDECISIVENESS, nearly everyday
9. recurrent THOUGHTS OF DEATH, SUICIDAL IDEATION without a specific plan, SUICIDE ATTEMPT or a specific plan for committing suicide
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HPA axis in depressed people
negative feedback features of HPA axis appear to be IMPAIRED
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why is negative feedback in depressed people impaired?
because BLOOD CORTISOL concentrations are often HIGHER in depressed than in non-depressed individuals
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blood cortisol levels in depressed people...
are HIGHER than normal
impaired negative feedback
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thyroid function in depressed people
low
although TRH and TSH are usually within the normal range in depressed patients, the THYROID RESPONSE to TSH is SIGNIFICANTLY LOWER in depressed patients
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what accounts for decreased thyroid function in depressed people?
not TRH and TSH levels - these are usually within the normal range
its the THYROID RESPONSE to TSH that is significantly lower
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lower thyroid response to TSH in depressed people suggests...
some SUBCLINICAL ENDOCRINE MALFUNCTION
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4 things related to THYROID that depressed people often exhibit...
1. very high level of ANTIBODIES against thyroid gland
2. high TRH concentrations in CEREBROSPINAL FLUID
3. enhancement of ANTIDEPRESSANT EFFICACY by co-treatment with TRIIODTHYRONINE (T3)
4. MOOD of depressed patients with HYPOTHYROIDISM IMPROVES when they begin THYROID TREATMENT
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treating depressed patients with thyroid hormones only works if...
the patient has hypothyroidism
can't simply give a depressed person T3 or T4 and expect them to get better
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estrogen and depression
DEFICITS in estrogen have been associated with depression
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estrogen and depression: double blind study SETUP
double blind
ESTROGEN TREATMENT was given to women who were hospitalized with severe depression
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estrogen and depression: double blind study RESULTS
none of the women who received placebo treatment showed mood changes
actually, 47% of those patients deteriorated in mood
BUT over 90% of the depressed women treated with estrogen significantly improved
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estrogen and depression: double blind study - what happened to the women treated with estrogen?
90% of the depressed women treated with estrogen significantly improved
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estrogen and depression: double blind study -women with history of past depression who were crossed over from estradiol to placebo patches
experienced a SIGNIFICANT INCREASE in depression symptoms
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PTSD
psychiatric disorder that may occur following experience/witnessing of life-threatening events
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PTSD symptoms
1. RELIVING the experience (nightmares, flashbacks)
2. SLEEP disturbances
3. feelings of DETACHMENT (feeling world is unreal, out-of-body experiences, estrangement)
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holocaust survivors with PTSD displayed...
1. LOW URINARY CORTISOL EXCRETION
2. IMPAIRED MEMORY
compared with Holocaust survivors without PTSD or healthy Jewish adults
COMBAT VETERANS displayed similar HPA axis deregulation
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in cognitive tests, Vietnam veterans with combat-related PTSD also displayed...
significant DEFICITS in SHORT-TERM MEMORY
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several fMRI studies have revealed that...
people suffering from PTSD have SMALLER HIPPOCAMPI than age-matched individuals without PTSD
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what do correlations between hippocampal volume and severity of PTSD symptoms show?
correlation of HIPPOCAMPAL VOLUME and PTSD SEVERITY reveal SIMILAR RELATIONSHIPS in Vietnam combat veterans and their non-combat brothers
suggests that having a small hippocampus might be a RISK FACTOR for PTSD, rather than a result of PTSD
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brain imaging of hippocampal volume and PTSD severity suggests that maybe...
having a small hippocampus is a RISK FACTOR for PTSD
rather than a result of it
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PTSD and GABA-benzodiazepine binding
veterans with PTSD showed LESS GABA-benzodiazepine binding
in a PET-scan throughout the brain
but ESPECIALLY in hippocampus, insula, thalamus, PFC, temporal and parietal cortices
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veterans with PTSD showed LESS GABA-benzodiazepine binding in a PET-scan - in WHICH BRAIN REGIONS?
all throughout the brain
but especially in:
a) hippocampus
b) insula
c) thalamus
d) PFC
e) temporal cortex
f) parietal cortex
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GABA
the principle inhibitory neurotransmitter in the brain
it exerts control over EXCITABILITY of brain areas
220
what does GABA exert control over?
the excitability of brain areas
and there's less GABA-benzodiazepine binding in veterans with PTSD
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alterations in GABA-ergic systems have been implicated in...
the PATHOGENESIS of anxiety disorders
including PTSD and depression
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seasonal affective disorder aka
winter depression
SAD
223
SAD is characterized by...
1. depressed affect
2. lethargy
3. loss of libido
4. hypersomnia
5. excessive weight gain
6. carb cravings
7. anxiety
8. inability to focus attention/concentrate
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when does SAD occur
late autumn and winter
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SAD prevalance rates
1% to 10%
higher prevalence rates:
a) at higher latitudes
b) in women
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tryptophan
amino acid that normally circulates in the blood at low concentrations
converted to serotonin in the brain
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what leads to higher tryptophan in blood?
1. diet consumption of carbs - stimulates pancreas to secret insulin
2. insulin facilitates uptake of sugars and non-tryptophan amino acids into peripheral cells
3. this action leads to HIGHER TRYPTOPHAN IN BLOOD
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carb ingestion seems to result in more...
tryptophan crossing the blood-brain barrier
this results in HIGHER SEROTONIN PRODUCTION
serotonin = generally associated with a decrease in appetite
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what results in higher serotonin production
carb intake
because eat carbs - insulin is released
insulin = uptake of sugars and non-tryptophan amino acids in peripheral cells
results in higher tryptophan in blood
higher tryptophan = more serotonin in blood
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higher serotonin means decreased...
appetite
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pateints with SAD have cyclic disruptions in what?
in their SEROTONIN-CARBOHYDRATE REGULATING MECHANISMS
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those with SAD have more...
serotonin transporter (5-HTT) activity during the autumn than the spring
more transporters = less serotonin available in the synaptic cleft
serotonin re-uptake is higher during the winter
(cyclic disruptions in their serotonin-carbohydrate regulating mechanisms)
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serotinin is converted to melatonin where?
in the pineal gland
234
melatonin concentrations are higher...
during the night than during the day
235
in patients with SAD, serotonin reuptake is higher when?
during the winter
because there's more serotonin transporter (5-HTT) activity during this time
more transporters = less serotonin available in synaptic cleft
since serotonin is associated with a decrease in appetite, lower serotonin means INCREASED APPETITE
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whyt do people with SAD have increased appetite?
because they have more serotonin transporter (5-HTT) activity in the winter
and more transporters mean less serotonin available in the synaptic cleft
and since serotonin decreases appetite, since there's more serotonin there's less appetite decrease
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current SAD treatment
light treatment is best
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SAD prior treatment ideas
before light treatment, it was thought that...
changing the ONSET OF SLEEP would be ideal in entraining circadian rhythms (biological clocks)
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light treatment at different times of the day results in differing...
rates of mood improvement
evening: no mood benefits
morning: (for a few hours) results in signs of REMISSION of the SAD symptoms
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a few hours of bright light SAD treatment usually...
results in signs of SAD symptom remission
within a few days
241
why do males (and females) abuse androgens?
1. enhance body muscle mass
2. enhance athletic performance
242
adverse behavioural effects of androgen usage
1. hyper aggression (including criminal violence)
2. major psychiatric symptoms
a) mania
b) hypomania
243
4 psychological variables that modulate stress phsyiology
1. control
2. predictability
3. outlets for frustration
4. habituation
244
interventions to reduce effects of stress on brain
1. regular physical activity
2. mindfulness-based stress reduction
3. social support and integration
4. developing sense of meaning and purpose
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control and modulation of stress
people suffer fewer stress-related pathologies if they can control the situation causing the stress
controlling a stressful situation is a type of COPING behaviour
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predictability and modulation of stress
predictability reduces stress response
knowing what to except allows you to prepare
whereas unpredictable stressors activate FIGHT-OR-FLIGHT response
depending on magnitude, can have long term consequences
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outlets for frustration and modulation of stress
ability to engage in displacement behaviour
having an "outlet"
ie. engaging in a hobby or moderate exercise
even modest activity can lessen effects of stress
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habituation and modulation of stress
learning that a stimulus that was originally perceived as a stressor IS NOT A STRESSOR
important way to modulate stress response
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lecture overview
1. EPIGENETICS describes processes by which LASTING CHANGES in GENE EXPRESSION can be accomplished without a change in DNA sequence
2. epigenetic mechanisms mediate interplay between NATURE and NURTURE - thus epigenetic investigations can focus more on GENETIC side of things, or ENVIRONMENTAL side of things
3. experiences are MEDIATED by HORMONES, which can lead to long-lasting ALTERATIONS
4. MOOD DISORDERS are characterized on a CONTINUUM and are influenced by hormones
5. CORTISOL, SEROTONIN, MELATONIN, ANDROGENS are all correlated with series of mood disorders
