stress and hormones Flashcards
review of transcription and genetic translation
- to synthesize mRNA, the two strands of DNA must be unraveled by enzymes called HELICASES
- gene consists of unique linear sequence of DNA (special marker sequences denote the start/end points of each gene)
- PROMOTER/FACILITATORY region marks the start of the gene
- binding of a TRANSCRIPTION factor to promoter allows enzyme RNA POLYMERASE to attach to promoter and begin process of DNA SYNTHESIS
- sequence of RNA nucleotides (determined by sequence of nucleotides along the DNA) eventually determines sequence of AMINO ACIDS in the PROTEIN product of the gene
- DNA METHYLATION and HISTONE MODIFICATION are EPIGENETIC processes
- DNA methylation is a process of LONG-TERM GENE SILENCING that involves adding a methyl group to cytosines in the promoter version of a gene
transcription versus translation
- transcription:
converts DNA into mRNA - translation:
decodes mRNA into amino acids, forming proteins essential for life functions
helicases
the enzymes that unravel the two strands of DNA
because DNA must be unraveled in order for it to be synthesized
genes consist of unique…
linear sequences of DNA
what marks the start of a gene?
promoter/facilitatory region
binding of what to the promoter allows RNA polymerase to attach and begin RNA synthesis?
transcription factor
what determines the sequence of amino acids in the protein product of the gene?
the sequence of RNA nucleotides
which is in turn determined by the sequence of nucleotides along the DNA
DNA methylation and histone modification are what kind of processes?
epigenetic
DNA methylation
process of long-term gene silencing
involves attaching a methyl group to cytosines in the promoter region of a gene
percentage of acute myocardial infractions (AMIs - heart attacks) are associated by patients to specific stress triggers?
48%
wars, natural disasters, anxiety-provoking events are associated with increase in heart attack rates
4 main questions in the behavioural endocrinology of stress
- why are some groups/individuals affected more severely by a potentially stressful event than others?
- are there differences among individuals in perception of stressors, perturbations to homeostasis, and physiological, psychological and behavioural responses to stressors?
- are stress responses always detrimental, or can they be adaptive in some circumstances?
- how can we measure stress?
homeostasis
the ability to maintain optimal conditions in the body
hormones are critical in this process
homeostasis involves the regulation of…
fluid and sodium balance
energy balance
eating
body mass and temperature regulation
stressors and homeostasis
stressors typically disrupt homeostasis
this affects the brain and behaviour
important to note: brain itself can perceive psychological factors as stressful and evoke a stress response
3 main sources of stressors
- environmental factors:
temperature extremes, noises - physiological factors:
insufficient food quality/quantity, water deprivation - psychosocial factors:
maltreatment, social subordination, novel situations, lack of control
stress
any significant disturbance of homeostasis
ie. extreme temperatures, psychological factors
stressor
condition, agent or other stimulus that causes stress in an organism
stress-response
suite of physiological and behavioural responses that help to re-establish homeostasis
flight or flight response
automatic and endocrine responses that prepare an individual to battle or flee from real or perceived threat, attack or harm
examples of systems involved in mediation of stressors
glucocorticoids
sympathetic/parasympathetic transmitters
cytokines
metabolic hormones
systems that mediate stress operate as a nonlinear….
nonlinear, interactive network in which mediators UP and DOWN-REGULATE one another
depending on factors like:
1. concentration
2. location in the body
3. sequential and temporal patterning
two systems that constitute the major components of the stress response
- system involving epinephrine/adrenaline
- from adrenal medulla - system involving norepineprhine/noradrenaline
- from adrenal cortex
emergency theory
within seconds of perceiving a stressor:
- sympathetic NS begins to secrete norepinephrine
- adrenal medullae begin to secrete epinephrine
immediate and non-specific component
involved in changes in:
a) cardiovascular tone
b) respiration rate
c) blood flow to muscles from trunk that support fight or flight behaviours
modern perspectives on stress = less likely to focus on fight or flight than on…
psychological features of stress
namely the degree of control the stressed individual has over the situation
exam: epinephrine and norepinephrine levels
epinephrine and norepinephrine levels increase and peak on the day of the exam
and then fall afterwards
parachute jump: hormone levels
cortisol, growth hormone and epinephrine all increase at the time of the jump
testosterone drops though
Hans Selye (1930s) is considered the…
founder of modern stress research
he was the first to observe epinephrine and glucocorticoid release in response to virtually any stressor (shows that stress response is NON-SPECIFIC)
common endocrine event underlying very different stress responses is…
release of glucocorticoids from adrenal cortex
caused by stressors as diverse as frostbite, formaldehyde exposure, hemorrhage
the two primary “stress hormones”
epinephrine and cortisol
despite facts that:
- their major endocrine functions involve metabolism
- circadian variation in these hormones occurs even in absence to stress exposure
both rats with ovarian hormone injection AND saline injection…
developed peptic ulcers, adrenal hypertrophy, regression of immune organs
was probably the handling of the animals in the lab that was causing them stress - not the injections
prolonged stress response - the _______ _______ syndrome
general adaptation syndrome
general adaptation syndrome consists of 3 stages…
- alarm reaction stage
- stage of resistance
- stage of exhaustion
alarm reaction stage
initial phase of body’s response to stress
stressor is perceived - body activates fight or flight response
^involves release of stress hormones (epinephrine, cortisol)
physiological changes occur rapidly (increased heart rate, heightened awareness, mobilization of energy reserves)
all to prepare the body to cope with the stressor
stage of resistance
if stressor persists beyond initial alarm reaction stage…
body enters stage of resistance
during this phase, body tries to adapt to ongoing stressor
by maintaining elevated levels of hormones and physiological responses
body tries to cope with stressor and restore homeostasis
stage of exhaustion
if stressor persists for extended period of time OR if body’s resources become depleted…
stage of exhaustion occurs
body’s ability to cope with stressor diminishes
physiological resources are depleted
Chrousos definition of stress
“the recognition by the body of a stressor and therefore, the state of heightened homeostasis. this way the stressors are threats against homeostasis; and adaptive responses are the body’s attempt to counteract the stressor and reestablish homeostasis”
Sapolsky definition of stress
“anything that throws your body out of homeostatic balance. considered together, stress is the sum of all nonspecific effects of factors that can act on the body to increase energy consumption above some resting, or basal, level.
in the short term, the stress response is adaptive and helps individuals cope with emergency situations; in the long term, the stress response tends to be maladaptive”
3 limits to the homeostatic concept of stress
- doesn’t address issue that PSYCHOLOGICAL stressors can evoke a full stress response; this psychological stress response actually causes HOMEOSTATIC IMBALANCE in an individual, rather than restoring it
- doesn’t account for INDIVIDUAL VARIATION in perception of stressors
- for a definition of stress to be useful, must address how the SAME STIMULUS can be STRESSFUL to one individual and PLEASURABLE to another
stress is a condition in which individuals are aroused by…
aversive stimuli
for an event to be defined as stressful, the individual must…
perceive it as aversive
a stressful event involves an individual’s lack of…
perception of control over the aversive stimuli
predictive homeostasis
the response range that comprises daily and seasonal variation in a given hormone
reactive homeostasis
range of mediator fluctuations necessary to respond to threats
allostasis
homeostatic overload
values above the reactive homeostasis range
allostatic load/overload
homeostatic failure
mediator values below the predictive homeostasis range
allostatic load/overload
physiological effects of stress response: within seconds…
- sympathetic NS secretes norepinephrine and epinephrine
from adrenal medulla
physiological effects of stress response: after release of epinephrine and norepinephrine…
HPA axis: hypothalamus releases cortico-tropin releasing hormone
this stimulates release of adrenocorticotropin hormone from anterior pituitary gland
within minutes, adrenal cortex begins to secrete glucocorticoids
3 main events of hormone release immediately after stressor presentation
- sympathetic NS (adrenal medulla) releases norepinephrine and epinephrine
- hypothalamus releases corticotropin-releasing hormone - stimulates release of adrenocorticotropin hormone from anterior pituitary
- adrenal cortex begins to secrete glucocorticoids
other hormones secreted from endocrine tissues during a stress response
prolactin
urocortin
glucagon
thyroid hormones
vasopressin
7 steps of the physiological stress response - zebra being hunted example
- need quick energy supply in order to sustain sprint back to a safe place
- immediate release of catecholamines (NE and EP) raises respiration and cardiovascular rates within seconds - body requires increased energy availability to sustain these high rates
- immediate increase in glucose and oxygen levels available in the blood
- EP increases delivery of oxygen to tissues and raises sympathetic tone
- glucocorticoids (secreted within minutes - likely only after stressful event) act on metabolic pathways to replenish energy reserves used to escape predator
- rapid effects of glucocorticoids operate via non-genomic pathways to affect behavioural stress responses
- although genomic pathways mediate some of the long-term effects of stressors - responses to injuries that might curtail movement (ie. pain, inflammation) are inhibited by the stress-induced release of endorphins and endocannabinoids
- energetically expensive activities like growth and reproduction, and some components of immune function, are also suppressed until after emergency has passed
- other components of immune function, like trafficking of immune cells to the skin where injuries might occur, are enhanced during stressful events
what happens to parasympathetic tone and metabolic rate as stress response subsides?
parasympathetic tone increases
metabolic rate returns to baseline
stress response: release of catecholamines does what?
catecholamines: NE and EP
raises respiration and cardiovascular rates within seconds
(body needs increased energy availability to sustain these high rates)
raised respiration and cardiovascular rates require…
increased energy availability
immediate increase in available levels of glucose and oxygen in blood
EP increases delivery of oxygen to tissues, raises sympathetic tone
rapid effects of glucocorticoids operate via…
non-genomic pathways
to affect behavioural stress responses
(although genomic pathways mediate some long-term effects of stressors)
what energetically expensive activities are suppressed until after the emergency has passed?
growth
reproduction
some components of immune function
stress response: endorphins and endocannabinoids do what?
stress-induced release of endorphins and endo-cannabinoids
in response to injuries that might curtail movement (pain, inflammation)
adaptive effects of proper stress response
- increased immediate availability of energy
- increased oxygen intake
- decreased blood flow to organ systems not needed for movement
- inhibition of energetically expensive processes that are not related to immediate survival, such as digestion, growth, immune function and reproduction
- decreased pain perception
- enhancement of sensory function and memory
stress response: both the predator and prey…
experience similar acute stress responses during the chase
despite their disparate roles
another example of non-specificity of stress response
epinephrine is what kind of molecule?
polar
epinephrine, as a polar molecule, doesn’t easily…
cross the blood-brain barrier
so glucocorticoids are good candidates for mediating behavioural effects of stress
evidence for glucocorticoid importance in behaviour
- these steroid hormones are released in response to numerous stressors
- steroid hormones can easily diffuse past blood brain barrier
- there are glucocorticoid receptors in several brain regions
implication of a hormone in behaviour requires evidence of…
hormonal signalling in the CNS
not only glucocorticoids act in the CNS during stress response - what else does?
CRH (a polypeptide)
corticotropin releasing hormone (CRH) mediates aspects of stress response…
adaptive and pathological responses
actes in hypothalamus and amygdala
CRH in hypothalamus
mainly involved in regulation of HPA axis
CRH in amygdala
involved in mediating anxiety responses
transgenic mice that express high levels of CRH in the amygdala…
are more ANXIOUS in a novel environment than control mice
same is true of wild-type mice/rats that are injected with exogenous CRH
CRH receptor antagonists decrease…
anxiety normally associated with alcohol withdrawal and social defeat in rats and mice
high levels of CRH expressed in transgenic mice also decrease…
female sexual receptivity
this isn’t reversed by adrenalectomy
CRH1 knockout mice…
were less anxious
CRH1 receptors seem to mediate…
hormonal, behavioural, and nociceptive responses to stress
appear to be involved in NEGATIVE FEEDBACK regulation of the HPA axis
role of CRH1 in negative feedback - hippocampus and maybe amygdala
notion that hippocampus and maybe the amygdala provide role in negative feedback during stress response
supported by CRH1 receptors that are located in these regions
receptors are presumably inactivated by conditional gene inactivation
activation of CRH2 receptor suppresses…
food intake in food-restricted and freely fed mice
suggests a mechanism for how stress suppresses appetite
how many CHR2 genes exist in mammals? what happens if all three are deleted?
three
if all three are deleted, knockout mice fail to recover from stress
display enduring anxiety responses
corticosteroid receptors in hippocampus
type I - mineralocorticoid receptors (MRs)
type II - glucocorticoid receptors (GRs)
mineralocorticoid receptors
type I corticosteroid receptors
have higher affinity for circulating glucocorticoids
usually engaged under baseline conditions
activation of these receptors is thought to modulate homeostatic balance
but, as glucocorticoids increase during a stress response, low-affinity GRs are activated
glucocorticoid receptors
type II corticosteroid receptors
low-affinity receptor (ie. more specific to cortisol)
provides negative feedback and brings the stress response back under control
role of aldosterone in stress response
aldosterone is a mineralocorticoid
central role in homeostatic regulation of:
1. blood pressure
2. plasma sodium (Na+)
3. potassium (K+)
are endo-cannabinoids involved in stress response? if so, how?
yes
endo-cannabinoids mediate the effects of glucocorticoids on stress response
via synaptic mechanisms
glucocorticoid and endo-cannabinoid interactions
- glucocorticoids bind to membrane-bound glucocorticoid receptors
- g protein signalling cascade induces endo-cannabinoid ligand production
(no gene transcription in this process - non-genomic) - endo-cannabinoid ligand molecules are released into the synapse
- they bind to CB1 cannabinoid receptors on GABA-ergic terminals to inhibit GABA secretion
- the decrease in GABA disinhibits norepinephrine secretion and modulates stress responses
remember: GABA is an inhibitory neurotransmitter AND there are glucocorticoid receptors in the membrane too
although ACTH is the pituitary hormone that is most often associated with stress, several other pituitary hormones, including… play important roles
vasopressin
prolactin
endorphins
enkephalins
vasopressin role in stress
increased blood concentrations of vasopressin in response to stress
directly affects behaviour
ENHANCES MEMORY CONSOLIDATION and RETRIEVAL
increases AGGRESSION in defence
works in concert with CRH to augment release of ACTH from anterior pituitary
urocortin role in stress
urocortin is a CRH-like neuropeptide
amplifies stress signals by activating CRH receptors
prolactin role in stress
suppresses reproduction temporarily
by acting at multiple sites within the hypothalamus-pituitary-gonadal (HPG) axis
endorphins/enkephalins role in stress
provide relief from PAIN
suppress gonadotropin-releasing hormone (GnRH)
thereby inhibit reproductive function
glucagon role in stress response
alpha cells of endocrine pancreas are stimulated to secrete glucagon
glucagon increases energy availability
beta cells of pancreas are inhibited by glucagon - from secreting insulin
adaptive-stress response
ideally, stress reponse is initiated by stressful stimuli
and then the system deactivates
negative feedback
what factors can deregulate the normal stress response?
- chronic stress
- genetic differences in glucocorticoid receptor numbers/subtype
- other individual diffs in:
a) endocrine secretion
b) responsiveness
c) carrier-binding proteins
this provokes inappropriate/pathological stress response
prolonged stress shifts the useful, adaptive short-term stress response to a…
pathological condition
can jeopardize health, economics, survival
4 health conditions associated with high levels of childhood stress
- asthma
- depression
- diabetes
- cardiovascular conditions
acute versus pathological effects of long-term stress responses
actue stress response:
a) shift from energy storage to energy use
b) increased cardiovascular tone
c) inhibited digestion
d) inhibited growth
e) inhibited reproduction
f) altered immune function and inflammatory responses
g) enhanced cognition
h) enhanced analgesia
pathological state associated with chronic stress:
a) fatigue; myopathy; steroid diabetes
b) hypertension
c) peptic ulcers
d) psychosocial dwarfism
e) impotence; anovulation; loss libido
f) impaired disease resistance; cancer
g) accelerated neural degeneration during aging
brain: effects of pathological state of stress
dendritic atrophy
impaired neurogenesis
impaired synaptic plasticity
enhanced benzodiazepine tone
heart: effects of pathological state of stress
basal hypertension
sluggish responses to and recovery from stress
pathogenic cholesterol profile
ovary: effects of pathological state of stress
decreased levels of gonadal hormones
increased risk of anovulation and miscarriage
immune system: effects of pathological state of stress
basal immunosuppression
decreased immune responsiveness to challenge
adrenal glands: effects of pathological state of stress
elevated basal levels of glucocorticoids
sluggish response to and recovery from stress
feedback resistance
testis: effects of pathological state of stress
testicular trophy
decreased levels of hormones of the gonadal axis
myopathy: pathological effects of stress response
muscle loss
with prolonged glucocorticoid secretion
inevitable
stress-induced breakdown of glycogen and lipids to elevate blood glucose concentrations cannot continue indefinitely
severe cases of stress-induced myopathy can induce…
irreversible loss of muscle cells in the heart
myopathy is an example of what we called ____ ___ ____ stress
Wear and Tear
reproductive function: pathological effects of stress response
reproductive function is inhibited by high glucocorticoid concentrations
and psychological stress can reinforce its effects
psychological stress of experiencing infertility, in addition to stress of treatments, causes more stress and consequently reinforces the infertility
inhibited digestion: pathological effects of stress response
prolonged inhibition of digestion during stress can lead to:
a) ulcers
b) chronic IBS
in concert with immune suppression - can allow bacteria to attack stomach
growth and repair processes: pathological effects of stress response
ie. fingernails are more flimsy/brittle, hair grows slower during stressful periods of life
chronic stress delays cutaneous wound healing
glucocorticoid inhibitory effects on broad range of immune responses
because of their inhibitory effects on multiple types of immune cells
glucocorticoids = remarkably efficacious in managing many of the ACUTE DISEASE MANIFESTATIONS of inflammatory and autoimmune disorders
example of an autoimmune disease that’s treated with glucocorticoids
lupus
chronic stress alters the ____ and ____ of the brain
structure and function
a) reduced neurogenesis
b) retraction of dendrites of hippocampal and cortical neurons
c) but expansion of dendrites in basolateral amygdala
d) increased inflammation in the brain
structure/function of which brain areas are particularly altered by chronic stress?
hippocampus
amygdala
PFC
strange: stress usually results in dendrite retraction, but in what area is it associated with physical expansion of dendrites?
basolateral amygdala
changes in brain following chronic stress are potential ways in which stress can lead to…
cognitive dysfunction
depression
why do our minds go blank when we get stressed? ie when taking a test
because stress deactivates the PFC
adaptive: to not be scared by a predator/threatening situation
hippocampus and HPA regulation: hypercorticolism
hippocampus = key site of HPA axis negative feedback
and hippocampus is damaged by chronic stress
vicious cycle can develop
- prolonged elevated glucocorticoids cause hippocampal dysfunction and impair negative feedback
- this in turn leads to ever-increasing glucocorticoid concentrations
blunted HPA axis responsiveness
normal response has a peak in glucocorticoids and then a sharp decrease
blunted/disrupted negative feeback:
a) glucocorticoids don’t reach the peak that occurs in normal response
b) they stay elevated for too long
hippocampus and HPA regulation: differences due to SOCIAL DOMINANCE
feedback system implicated in cortisol response can vary according to social position
stress has diff effects on dominant/subordinate baboons
diff effects of stress on dominant versus subordinate baboons
after stressful event:
- dominant animals display ELEVATED CORTISOL
- but because they have an efficient HPA axis feedback system, cortisol concentrations return to baseline faster - subordinate individuals have blunted sensitivity to CRH in anterior pituitary
- thus, a similar stressful stimulus results in LOW CORTISOL RESPONSE
- but also LONG TERM ELEVATION OF GLUCOCORTICOIDS
may ultimately harm these individuals
for something to be considered stressful, individuals must… but…
perceive the stressor as aversive
but humans = exposed to diff circumstances that aren’t necessarily perceived as stressful but that can have deregulatory effects on physiological responses that aim to restore homeostasis
adversity can be conceived as the exposure to harmful/threatening stimuli, or the absence of stimulation needed for typical development
two ways to conceive ADVERSITY
- exposure to harmful/threatening stimuli
- absence of stimulation needed for typical development
adverse exposure forms
exposure to harmful/threatening stimuli
or absence of stimulation needed for typical development - which in turn will require SIGNIFICANT ADAPTATION by the infant
two effect levels of adverse exposure forms
- direct effects:
a) family psychiatric problems
b) maltreatment
c) family functioning
d) witnessing/suffering domestic violence - contextual effects:
a) growing up in poverty
b) living in violent areas
c) occupational disruptions
Romania’s example of negligence: the policy
70’s-80’s : President Nicolae Ceausescu created policy aimed at increasing population
plan was to increase pop from 23 to 30 million by 2020
prohibition of contraception and criminalization of abortion
specific state laws for women’s health, requirements for examination by state doctors
Romania’s example of negligence: the policy’s effects
it “worked”
birth rate increased from 1.9 births per woman to 3.6 in one year
but people were poor - no money to support children
left them on street
Romania’s example of negligence: orphanages
government created orphanages to house the abandoned children
employees of these shelters = instructed not to show any affection to babies
if crying, told to ignore them until they “learned it wouldn’t get them attention”
slept in identical cradles, lined up in large sheds - little human contact
The Bucharest Project
randomized controlled trial of foster care as an ALTERNATIVE to institutionalized rearing of abandoned children
changes in ANS and HPA axis measurements during 2 tasks
a) two social stressors (the Trier Social Stress Test - TSST) which includes preparation, speech, and math portions
b) nonsocial stressor (frustration task)
assigned to 3 intervention groups:
a) deprived from care
b) high quality foster care intervention
c) typically developing Romanian
The Bucharest Project findings
group differences in ANS reactivity to stressor tests
care as usual group
foster care group
never institutionalized group
- children who remained in institutional care exhibited significantly blunted HPA AXIS REACTIVITY
- children who remained in institutional care exhibited significantly blunted SYMPATHETIC RESPONSE
importance of child attachment for the HPA axis
parent and child relationship is crucial for infants
secure versus insecure attachment
children with more secure attachment have better stress response
