Stress Flashcards
what are the 2 glucocorticoids receptors
GR and MR
what type of receptors has faster effect than the other?
membrane receptors have faster effect than genomic receptors
what protein are the GCs cytosolic receptors associated with?
heat shock protein
what are the genomic actions of glucocorticoid receptors?
direct: translocation to nucleus where it dimerizes and binds to GRE/MRE -> transcription
indirect: production of second messengers that have nuclear actions
what 2 types of receptors mediate GC negative feedback on the HPA axis?
classical cytosolic receptors and membrane receptors
what are examples of the non-genomic actions of GC receptors
- translocation to mitochondria affecting calcium
- endocannabinoids production
- modulation of endogenous signaling molecules like NO
what molecule is used for GC membrane receptors negative feedback actions?
endocannabinoids
what are the 4 signaling outcomes from subcellular GR distribution
- ligand-activated nuclear GR causes changes in gene transcription/expression
- ligand-activated GR translocates to the mitochondria to regulate ATP production and cytochrome C release
- ligand-activated GR signaling from a membrane origin can modify the actin cytoskeleton and enhance post-synaptic dendritic spines formation
- post-synaptic membrane GR can enhance AMPA receptor subunit transport to the active site to facilitate neurotransmission
or diminish neurotransmission by suppressing the release of excitatory neurotransmitter (glut)
what kind of messengers are endocannabinoids? what type of receptor do they employ?
retrograde messenger. lipid-derived transmitters
G-protein coupled receptors.
name the 2 endocannabinoids and which one has higher levels
Anandamide (AEA) and 2-AG (higher levels)
name the endocannabinoid receptors and their affinity.
CB1R: high AEA affinity, moderate efficacy
CB2R: moderate affinity and high efficacy for both 2-AG and AEA
what triggers endocannabinoid production?
GCs binding to membrane receptors
where are CB1Rs located and what do they do at each location to inhibit HPA axis?
PVN: regulate CRF neurons activity (Glu and GABA neurons)
Pituitary: reduces cAMP induced by CRFR1 (reduces ACTH production)
Adrenal: reduces cAMP induced by MC2R activation in the cortex, reduces EPI release from the medulla (reduces GC production)
CORT binding to mGR on post-synaptic CRF neurons induces endocannabinoid what?
induces endocannabinoid production, which then act on presynaptic glut neuron
where do endocannabinoids act and induce a fast and a slow signal, respectively?
fast action: In PVN through membrane receptors, reducing CRF expression
slow action: indirect regulation through PFC inhibits CRF secretion
what 3 things regulated glucocorticoids access to target tissues and GCRs?
- binding proteins (albumin and CBG)
- multiple drug resistance P-glycoprotein (MDRpG)
- metabolism by 11-hydroxysteroid dehydrogenase type 1 (11 HDS-1)
describe albumin and its interaction with GCs
GC binding protein that has low specificity, high capacity for GCs
describe CBG and its interaction with GCs
binding protein (corticosteroid binding globulin) has high specificity, low capacity for GCs. it only binds natural glucocorticoids (cortcosterone, cortisol, their 11-dehydro-metabolites), not synthetic (dexamethasone)
can unbound steroid enter the brain? what percentage of steroid in unbound?
yes. 5%
how does CBG interaction with GCs limits free cortisol increase?
free cortisol levels can only increase at GC concentration peaks, when CBG is saturated
what happens with CBG and GCs during fever (small temp rise)? c’est quoi le rapport avec l’inflammation?
decrease in CBG affinity for GCs (increase of GCs availability in the brain, GCs have anti-inflammatory effects)
what does MDRpG do?
actively transports synthetic steroids like dexamethasone and 17-hydroxylated natural steroids out of the brain (retards the entry of cortisol in the brain)
how is MDRpG expression after seizures?
upregulated
what is 11beta-HSD1?
enzyme in the CNS and in periphery that transforms inactive steroid into active form
name active and inert (inactive) steroids/glucocorticoids
active: cortisol, corticosterone, prednisolone
inactive: cortisone, 11-dehydrocorticosterone, prednisone
how did increase in 11beta-HSD1 affect obesity?
increased obesity, insulin resistance/diabetes
what can chronic elevated levels of circulating glucocorticoids cause?
metabolic syndrome: diabetes, obesity, cardiovascular diseases
what happens to fetuses with a deficient placental 11beta-HSD2?
inefficient barrier causes lot of active cortisol transferred to the fetus (bad)
do fetuses have 11beta-HSD1?
no (they can’t form active glucocorticoid. they get active cortisol from their own adrenal glands)
what happens to fetus who’s mother is treated with dexamethasone?
dexamethasone passes the placenta and increases glucocorticoid action on the fetus which reduces growth and alters developmental trajectory
how is placental 11beta-HSD2 mRNA expression in people with depression and anxiety?
lower (aka more cortisol in fetus)
how do antidepressants affect placental 11beta-HSD2?
increase its expression
are glucocorticoid levels higher when fasted or fed?
higher when fasted. higher GCs levels at wake to prepare to digest breakfast
how do the low levels of corticosteroids affect the body under a basal, fed state?
increases digestion, glycogen storage, hepatic fat synthesis, protein synthesis, insulin (substrate STORAGE- anabolic)
how do high levels of corticosteroids affect the body under stressed, fasted conditions?
decrease protein synthesis, glucose uptake, insulin level
increase protein breakdown, lipolysis, gluconeogenesis
(substrate SUPPLY - catabolic)
how does high and little stress affect food intake respectively?
little stress increases food intake
high/acute stress reduces food intake
how are MRs occupancy under basal conditions? what about GRs?
MRs are highly occupied under basal conditions. GR progressively become more activated and occupied
where are pyramidal vs granule neurons located in the hippocampus?
pyramidal neurons: CA1 and CA3
granule neurons: dentate gyrus
how does excess GCs affect hippocampal pyramidal cells?
reduces dendrites length (negative effect)
how does normal and excess GCs affect hippocampal granule neurons?
normal GCs levels are necessary for development and maintenance of dentate gyrus granule neurons.
Excess GCs can reduce neurogenesis.
how do GCs affect amygdala?
increases dendritic branching in basolateral amygdala pyramidal neurons (opposit of hippocampal pyramidal neurons)
in the hippocampus, can MR and GR occupancy have opposit effects?
yes they can
how does acute vs long-term serum GCs elevation affect host defense, CNS, and cardiovascular activities?
acute:
- host defense: protects from harmful inflammatory mediators
- CNS: improved cognitive functions
- cardiovascular: salt & water retention
long term:
- host defense: immunosuppression, poor tissue repair/wound healing
- CNS: mood changes, neurodegeneration
- Cardiovascular: hypertension
what type of stress can cause insulin resistance?
long term stress can cause insulin-resistant diabetes mellitus
what is the definition of allostasis?
The process of maintaining stability (homeostasis) by active means (i.e. secretion of cortisol, catecholamines to maintain balance)
what is the definition of allostatic load?
the wear and tear on the body and brain caused by the use of allostasis, particularly when the mediators are dysregulated (i.e. exaggerated cortisol secretion or delayed turn off the stress response)
what is the allostatic load index?
adding the scores of each measured biomarkers. used to determine what exactly underlines physiological dysregulation
how is cortisol secretion affected by mild stress?
only the lowest concentration of plasma cortisol throughout the day is increased
is the normal circadian cortisol secretion rhythm still present under high stress?
no it disappears
what happens to animals exposed to homotypic stressors?
they sensitize (their GCs response to stressor normalizes)
what happens to animals exposed to heterotypic stressors?
their stress response increases
what is the definition of allostatic load related to stress?
cumulative burden of chronic stress and life events
describe the normal allostatic load?
physiologic stress response initiated by a stressor, sustained for an appropriate interval, then turned off
give 4 examples of abnormal allostatic load
- repeated “hits” from multiple stressors
- repeated “hits” with lack of adaptation
- prolonged response due to delayed shut down (can’t turn off HPA axis)
- inadequate response (too small) causes compensatory hyperactivity of other mediators
what can be a reason for the HPA axis being unable to turn off?
reduced glucocorticoid sensitivity
what additional structures are recruited during chronic stress?
PVthalamus, amygdala, locus coeruleus (norepinephrine), bed nucleus of the stria terminalis (BNST
What do the additional recruited structures do during chronic stress?
maintain the changes in the HPA activity (increased)
what mediates the recruitment of additional structures in chronic stress?
tonically elevated plasma corticosteroids
what happens to GC negative feedback in the PVN under chronic stress?
GC ability to inhibit CRF is reduced under chronic stress
remember: what does GC do to CRF in the amygdala in normal condition?
what about under chronic stress?
opposit of the PVN: GC stimulates CRF in the amygdala.
under chronic stress, increased CRF in the amygdala indirectly stimulates PVN neurons via locus coeruleus
through what structure does increased CRF in the amygdala during chronic stress stimulate PVN neurons?
locus coeruleus (norepinephrine)
remember: what other hormone is increased by CRH?
AVP
name the cellular plasticity changes in parvocellular CRF neurons in the PVN after chronic stress exposure?
increased stimulation: increased glutamate and norepinephrine activation
reduced inhibition: reduced GABA inhibition, reduced GC negative feedback
what is dopamine beta hydroxylase?
DBH: enzyme that catalyzes the transformation of dopamine into norepinephrine
what plastic changes are seen in the dorsal hippocampus and in mPFC under chronic stress? what is the effect of this change?
dendritic atrophy(decrease) and decreased GR expression; decreases HPA feedback and memory
what plastic changes are seen in the basolateral amygdala under chronic stress? what is the effect?
increased dendritic branching and stress excitability -> increases HPA axis and memory
what plastic changes are seen in the PVN under chronic stress? what is their effect?
increased secretagogue synthesis, increased stress responsiveness, decreased GR expression;
increases the excitability to novel stress
what happens to neurons in mPFC after chronic stress?
dendritic atrophy and spine/excitatory synapse loss
what is chronic stress thought to do to glial cells?
reduce glial cells and their function in reducing synaptic glutamate concentrations (this increases excitatory glutaminergic response -> excitotoxicity)
briefly how do glial cells usually work?
they pump glutamate out of synapses to reduce excitation
which region of the hippocampus is associated with memory vs emotions?
dorsal = memory
ventral = emotions
in what case does chronic stress exceptionally reduce HPA axis instead of increase?
PTSD
how does chronic stress affect dorsal vs ventral hippocampus?
dorsal = decreases dendrites
ventral = increases dendritic branching
how is central CRF and HPA axis activity in depression?
high activity
which CRF-R1 vs CRF-R2 is implicated in depression vs anxiety?
CRF-R1 = depression
CRF-R2 = anxiety
what do antidepressants act on?
normalizing HPA function
what may be predisposing factors of stress and depression?
polymorphisms of GR
how does early life stress and depression modify HPA axis?
long term hypersensitivity to stress (increased ACTH and cortisol secretion)
what is special ab people with early life stress but not depression in their stress response?
increased ACTH secretion, blunted adrenal response / cortisol secretion
how do depressive patient respond to the DEX-CRH test?
deficient GC negative feedback (their cortisol levels are high even after DEX injection that should suppress HPA + exaggerated ACTH response to exogenous CRH)
how is the efficacity of antidepressive treatments related to?
normalization (decrease) of HPA axis activity
what are the 2 ways through which antidepressants enhance GC receptor-mediated actions?
- enhance receptor translocation into the nucleus
- stimulate the production of TFs that bind to GRE to increase transcription of specific genes
what are GREs? give an example
glucocorticoid responsive elements; BDNF
in what other way do classical antidepressants work?
increase serotonin and norepinephrine in synaptic clefts
name 4 future prospects for antidepressants
- increase 5-HT release and synaptic concentration
- increase neurotrophic factors like BDNF important for cellular plasticity
- CRF-R1 antagonists that reduce HPA axis
- MAPK inhibitors
how does early life trauma affect genetic? give an example
epigenetic changes modify gene expression ex:
- enhanced (GR) methylation (silenced),
- reduced AVP methylation in PVN (increase expression)
- apparition of different polymorphisms, ex GR and MR gene mutations
what is the presence of the parent in infancy necessary for?
to buffer HPA axis stress response
how might parental presence in infancy buffer HPA axis?
via reduction of norepinephrine release in hypothalamus and inhibitory effects of oxytocin on HPA
how can parents reduce HPA responses to TSST in middle childhood?
through the phone, not via text tho
when do parents loose their potency to buffer HPA axis?
in adolescence. they increase cortisol levels in children
what does the presence of the partner do in prairie voles after stress?
prolongs PVN OT release after stress (reduce HPA activity)
what is depression mostly caused by?
glutamatergic and gabaergic transmission imbalance
name one gene polymorphism associated with MDD
R23K
how does the neuroendocrine axe interact with peripheral immune cells?
via cytokines, vagus nerve activation, sympathetic and parasympathetic nervous system
for what hormones do lymphocytes, monocytes, and other immune cells express receptors?
corticosteroids, insulin, prolactin, growth hormone (GH), somatostatins, estrogens, testosterone, leptin, ghrelin, opioids, neuropeptide Y and vasoactive intestinal peptide (VIP)
name the 4 axes of hormonal and neuropeptide mediators interactions?
- hypothalamic-pituitary-thyroid HPT
- hypothalamic-pituitary-gonadal HPG
- hypothalamic-pituitary-adrenal HPA
- hypothalamic-growth-hormone
what hormones does the sympathetic system release?
catecholamines , epinephrine and norepinephrine
what hormones depress immune responses? which ones increase it?
depress: glucocorticoids, androgens
increase: estrogens, GH, thyroxine, insulin
what hormones are increases in the catecholaminergic pathway?
norepinephrine, epinephrine from adrenal medulla
name pro and anti-inflammatory cytokines
pro-inf: IL-1, IL-6, TNF
anti-inf: IL-4, IL-10, IL-1Ra, TGFB
what is IL-1ra? what receptor does it bind to?
a natural highly selective competitive IL-1 antagonist.
binds to IL-1R1
can IL-1R1 be activated alone?
no it requires association with an accessory protein
are IL-1 cytokines biologically active?
IL-1a and IL-1ra are biologically active.
IL-1B must be cleaved by caspase 1 to be active.
what is IL-1RII?
receptor for IL-1a and b that inhibits signal
what happens after IL-1RI activation?
recruitment of IL-1AcP, IRAK, activation of NF-kB TF
how do cytokines reach the brain?
- neural path: pro-inf cytokines stimulate afferent fibers in the vagus nerve -> activate NTS and area postrema
- humoral path: pro-inf cytokines cross leaky regions of BBB (ex choroid plexus and circumventricular organs) and activate endothelial cells
how does the area postrema contribute to brain stimulation by cytokines?
macrophages in area postrema can produce endogenous cytokines that can act at the NTS
name 2 mediators in the brain involved in fever
COX-2, PGE2
name 4 immune mechanisms that T3 and T4 modulate
- cell-mediated immunity
- NK cells activity
- IFN antiviral action
- T and B cells proliferation
how does hyperthyroidism affect immune system?
causes an abnormal antibody production, increased lymphocyte proliferation, and increased ROS production by macrophages
how does hypothyroidism affect immune system?
causes immune deficits
what are ER (estrogen receptors) effect on the immune system?
- ERa = stimulates immune cell proliferation
- ERB = promotes apoptosis and cell differentiation
how does testosterone affect the immune system?
it has a suppressive effect: lower response to pathogen, higher prevalence of infectious diseases, lower prevalence of autoimmune disease
how can pro-inflammatory cytokines affect endocrine functions?
can inhibit hypothalamic GnRH release
what kind of opposit effect do ERa have on immune system and in what conditions?
- short term effect: decrease inflammation and cytokines, decrease antigen presentation
- long term: increase inflammation and cytokines
what is androgen’s general effect on the immune system?
immunosuppression
what are IGF and IGFBP?
proteins via which pro-inflammatory cytokines affect bone integrity
what immune phenomenon is adrenal insufficiency associated with?
excess circulating lymphocytes
how did removing adrenal affect the thymus?
In animals, removal of the adrenal gland results in hypertrophy of the thymus, an organ responsible for the maturation of lymphocytes
what immune conditions can GCs be used to treat?
autoimmune and inflammatory diseases: prevents immune responses from overshooting
how does acute vs chronic stress affect inflammatory response?
- acute: enhances GR sensitivity -> limits NF-kb -> reduces pro-inflammatory cytokines
- chronic stress: steroid resistance -> increase NF-kb -> increase pro-inflammatory
basically what is the usual effect of stress on immune regulators?
reduction in pro-inflammatory cytokines and increase in anti-inflammatory cytokines
what is pro-inflammatory cytokine’s effect on HPA axis?
stimulate HPA axis.
anti-inflammatory do the opposit: reduce HPA axis
explain the negative feedback loop of GC and cytokines?
GCs stimulate anti-inflammatory cytokines, anti-inflammatory cytokines put a break on HPA axis
where does IL-1B act the most to stimulate HPA axis?
PVN
where does IL-6 mainly act to stimulate HPA axis?
pituitary
name microglia functions
- interact with immune cells
- produce cytokine, chemokines
- eliminate synapses and apoptotic cells
- involved in neuroprotection
- neurogenesis/neurodevelopment
what can activate microglia?
viral envelope, bacterial cell wall, infectious agents (ex prion), certain protein (ex amyloid beta)
what do high ATP levels do/signal in the brain?
- facilitate microglial reactions
- signal excessive cellular activity/damage
when/how does colonization of the gut first happen?
when child is exposed to vaginal microbiota (or skin microbiota in c-sections)
what processes require gut bacteria?
- brain development
- neuroplasticity
- microglia activation
- neurogenesis
in what 4 ways do the gut and CNS communicate?
- enteric nervous system
- parasympathetic (vagus) and sympathetic autonomic nervous system
- neuroendocrine
- neuroimmune signaling pathways
what alters our gut microbiome?
diet, drugs, infection, stress
how does the microbiota communicate with the brain?
- via vagus nerve
- microbial antigens that stimulate immune response (DCs secrete cytokines)
- microbial metabolites
- stimulate enteroendocrine gut cells to secrete hormonal messenger
what are microbial metabolites?
short chain fatty acids
give examples of peptide factors produced by enteroendocrine cells?
GLP-1, CCK, PYY
also catecholamines, GABA, tryptophan
what are the effects of microbiota on behaviour?
anxiety, sociality, modulate oxytocin, depression, visceral pain (ex IBS)
what happens to germ-free mice’s HPA axis?
they have an exaggerated HPA response to stress
what could possible be affected by maternal microbiota?
offspring behavior ex cause anxiety, depression
what happened to humans who injested administration of probiotic yoghurt or capsules containing Lactobacillus acidophilus LA5 and Bifidobacterium lactis BB12 for six weeks?
improved mental health
what can LcS (probiotic) do?
it suppressed stress-induced increases in glucocorticoid levels in both humans and rodents.
what are the 2 main genera of probiotics showing beneficial effect on mental health?
Bifidobacterium and Lactobacillus
difference between probiotics and prebiotics?
- probiotics = living microorganism that gives host health benefits
- prebiotics = nondigestible ingredients that are good for microbiome
what are gut problems often due to?
leaky gut barrier
what can inflammation in babies be a risk for (related to neuroimmune interactions)
risk factor for many mental disorders, ex schizophrenia
what mental disorders are cytokines and gut microbia associated with respectively?
cytokines = depression
gut = autism
who is more prone to neurodevelopmental (childhood onset) vs neuroaffective (pubertal onset) mental disorders?
men are more susceptible to neurodevelopmental.
women are more susceptible to neuroaffective.
what are symptoms of schizophrenia?
- hallucinations, delusions
- social dysfunction
- cognitive deficits
- prevalence in males
- development in late adolescence
what origin does schizophrenia stem from?
neurodevelopmental origin
what causes schizophrenia?
- genetic and environment
- defective connectivity between subcortical DA, thalamus, temporal-limbic areas and PFC
what early developmental factors can influence schizophrenia?
- prenatal event and genes can cause subtle motor, cognitive, social deficits
- chronic social adversity can cause social anxiety, depression
maternal infection contribute to what fraction of SCZ cases?
1/3
name examples of infections that can contribute to schizophrenia?
- viral: influenza, rubella, HSV2
- bacterial: pneumonia, pyelonephritis
how is the gut-brain axis modified in schizophrenia?
systemic inflammation causes leaky blood-gut and blood-brain barrier -> reaches astrocytes and microglia -> inappropriate pruning
what is elevated in clinical depression?
cytokines and cortisol secretion
treatments against what can cause depression?
recombinant human cytokines (IL-2, IFN-a) treatment against tumours and hepatitis C
name a pro and an anti-inflammatory cytokine increased in depression
pro-inflmmatory: IFN-Y, IL-6, TNF-a
anti-inflammatory: IL-10,
The brain of depressed patients also
presents signs of what?
increased inflammation
how can microbiome cause depression?
certain bacterial species promote inflammation and influence CNS
what are the 3 main communication routes between microbiome and CNs?
- soluble hormonal messengers
- neural projections
- immune cells and inflammatory cytokines
what is BDNF?
neurotrophic factors that can trigger a neurodegenerative cascade causing depression
how can probiotics help with depression?
can reduce systemic inflammation and gut leakiness (reduce mucosal barrier dysfunction)
what can bacteroides fragilis do in early life?
reverse gastrointestinal, microbiota, and selective behavioral changes (reverse autism)
