Wednesday, March 28, 2012

Stress III : Chronic Stress and Disease

1Summary¶

• There's a bunch of syndromes that come with stress. such as obesity, bad memory, etc
• lesson: relax and chill

2Basics¶

• some terms:
  • allostasis: a component of homeostasis: maintaining stability through change
  • allostatic load: consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress, leading to 4 possible conditions:
    • normal response repeated over time
    • lack of adaptation : (normally response show go down after a number of exposure to the same type of stress
    • prolonged response: recovery time takes too long
    • inadequate response: not responsive to stress anymore
• chronic vs acute stress:

• under chronic stress, tonically elevated plasma corticosteroids recruit additional neuronal structures (PVthalamus, amygdala, BNSt, locus coeruleus, etc) that project to PVN.
• chronic stress also lead to loss of circadian rhythm:
  • at mild stress level, only the lowest GC level in the rhythm is increased
  • at high stress level, the whole curve of cortisol level shift up and rhythm is lost.
• chronic stress leads to higher sensitivity to stress
  • rats after some habitual stress stimulus, when exposed to a second/novel stress stimulus, has much higher ACTH level than rats that have not have habitual stress stimulus.
    • this effect is more strongly manifested in young rats. because brains are more adaptive when they're young.

3Effects of Chronic Stress¶

• increase adrenal weight, decrease body weight (not always), increase plasma CORT (corticosterol) level, thymic weight stays about the same.
• hippocampus: dendritic atrophy and decrease GR expression (an effort to compensate elevated level of GC) -->decrease HPA feedback and memory
• medial prefrontal cortex: same as hippocampus
• central amygdala : amygdala enalarges and increase CRH release --> increased HPA and autonomic excitability and anxiety.
• thalamus PVN : increase stress excitability --> increased HPA excitability to novel stress and decreased HPA excitability to familiar stress (as discussed earlier)
• hypothalamus PVN: upregulate secretagogue synthesis, stress responsivenss, decrease GR expression --> increase excitability to novel stress.
• since projection to prefrontal cortex is the last one to mature in adultlescent, exposure to stress during development can impair adaptation to homotypic stress later on.

3.1Mechanism of damage caused by chronic stress¶

• elevated level of GC occupies GR, which induces apoptosis and exert an inhibitory effect on neurogenesis
  • activation of tumor suppressor protein p53, which suppresses Bcl2, an anti-apoptotic molecule
    • more proapoptosis molecules than anti-apoptotic molelcules
    • perturbation of mitochondrial transmembrane potential and release of cytochrome c
      • activation of caspase 9 (intrinsic pathway of apoptosis)
• extrinsic pathway of apoptosis: byGR recruits FADD which recruits caspase 8, which activates caspse 3, which activates Bid, which stimulates release of cytochrome c release
• both intrinsic and extrinsic pathway of apoptosis converges on caspase 3.
• induce cell cycle arrest
• decrease expression of BDNF (brain-derived neutrophic factor), which activates CREB
• GC action via MR can inhibit apoptosis.
• there's a fine balance between MR and GC regulation.

3.2chronic stress and gene-expression¶

• chronic sress leads to :
  • downregulation of MR and GR --> less effective negative feedback
  • CA3 dendritic tree atrophy
  • serotonin receptor downregulation
  • LTP (long term potentiation) is reduced --> cognitive impairment.
• this is done by epigenic change
  • potentially reversible
  • DNA methylation -- >silence the gene
  • histone modification at N-terminal tails
  • regulation by no-coding RNA (microRNA)
  • environmental influences on gene expression via epigenetic changes can persist even when initial trigger is gone.
  • inter-individual variability can be due to epigenetic variation and genetic sequence polymorphism, which contribute to vulnerability to diseases.
• example of mice:
  • mice whose moms licked them a lot while they were pups have more resistance to stress
    • they have less methylation on GR (more expression of GR)
  • wherease mice whose moms didn't licked them much cannot cope with stress as well
  • cross-fostering (licky-mom pups raised by non-licky moms) : show that offsprings raised by low-licky moms have more methylation on GR
    • epigenetic changes!

4Stress and depression¶

• depression is characterized by high central CRF activity and HPA axis activation
  • elevated cortisol
• CRF-R2: anxiety and CRF-R1: depression
• antidepressant normalize HPA function
• polymorphisms of GR might be predisposing factors
  • short nucleotide polymorphism in MR and GR
    • R23K : low cortisol response to TSST (trier social stress test). condition is similar to PBSP
    • Bell : hyperreactivity to stress due to poor negative feedback regulation
• early life stress and depression can modify HPA axis in the long term:
  • people who were abused as children and/or had major depressive disorder have elevated ACTH and cortisol level.

4.1Evaluation of negative feedback in HPA axis¶

• patients receive an oral dose of DEX (synthetic glucocoritcoid) at 11pm before the simulation
  • 11pm because that's the trough of cortisol level, where HPA should be most sensitive
• basal blood sample is drawn at 3pm the next day.
• CRH is then injected intravenously after 3pm and blood sample is collected at various time after.
• plasma ACTH and cortisol are measured
• result:
  • depressive patients have little negative feedback --> still high cortisol after DEX
  • depressive patients with hyperactive HPA axis and impaired glucocorticoid feedback have exaggerated ACTH response to CRH injection.
  • some depressive patients have lower cortisol and ACTH levels when given antidepressant, but for some antidepressants don't work.
• basically
  • DEX is used to bring down cortisol level first (to the lowest level) and to see how good the negative feedback is.
  • and then CRH is used to see how sensitive HPA axis is

4.2Activity of HPA axis in depression¶

• CRH binds CRH-R and induces anxiety, psychomotor activity, anorexia (a eating disorder), sleep disturbance
  • drug target CRH1R because it has to do with depression. or CRH2R for anxiety.
• vasopressin is also elevated during stress response and induces anxiety and enforces stress reaction
  • bind V1_A and V1_B receptors. not good for drug targets cuz vasopression also does other things
• cortisol : cognitive disturbance, psychotic, affective syndromes, metabolic syndrome, suppressed neurogenesis
  • glucocoritocid receptor antagonist as drug, but not reallly good because GC is also important to other normal fnctions and GR is everywhere in the body.
• stress inhibits BDNF (a growth factor, brain-derived neuorotrophic factor) which is supposed to increase serotonin release. so stress leads to depression (possibly)
• CRF pathways:
  • classical PKA acitvation and increase in cAMP and CREB after binding to CRFR1
    • in central amydala, hippocampus, hypothalamus, cortex
  • ERK pathway
    • in basal lateral, laterla amygdala, pparamedial cells (CA1, CA3)
    • mediates synaptic plasiticity, LTP in the amygdala
    • mediates proliferation and neuronal differentiation and effects of neurotrophins and growth factors
    • mediates actionof mood stabilizers in CNS (also used to treat depression)

5Antidepression drugs#¶

• how antidepressant drug can work:

  • enhance translocation fo GR receptor into the nucleus --> induces more negative feedback
  • stimulation of production fo transcription factors (like CREB, NGFIA) that would bind to GRE to induces transcription of some genes (like GR, so more GR to bind GC)

• a novel therapy : deep brain stimulation

  • deep brain stimualtion at nucleus accumbens, cortex, etc, can enhance production of BDNF from neurons with terminals at those region
    • alleviate depression
  • transmagnetic stimulation for resistance depression may increase neurogenesis, more dendrites.
  • mechanisms not well understood.
• future prospect of antidepressants:
  • increase serotonin (5-HT) release
  • increase BDNF and others for cellular plasticity (because depression is associated with decrease in plasicity and neurogenesis)
  • antagonist of CRF-R1 that can cross the blood brain barrier and resist degradation (because small peptides get degraded readily)
  • small cell permeable inhibitor of MAPK in conjunction with CRF antagonist to confer regional specificity
• target to CRF2R can reduce anxiety
  • and we know that UCN3 binds specificaly to CRF-R2 and has higher affinity than CRF.
  • UCN3 is an agonist of CRF-2R and can reduces anxiety.
    • evident in mice in maze experiment
    • UCN3 adminstered mice spend more time in open arm (light) than close arm (dark). less anxious about exploring the maze

6Stress, Obesity, Cardiovascular Diseases#¶

• high GC corresponds to catabolic state in acute response
• however, in chronic stress, high GC level promotes energy storage, which leads to obesity
  • white adipose tissue than produce more GC --> fatter :(
  • ADX animals (adrenal actomized) loss weigh
  • it's cuz stress makes the body think that we need more food to meet metabolic demand (since GC is catabolic)
• fat cells have :
  • P450 aromatase
    • converts testosterone to estradiol, androstenedione to estrone
    • mass of adipose tissue correlates closely to whole body steroid level
      • up to 100% estrogen and 50% testosterone in postmenopausal women are contributed by adipose tissue.
  • 11b-HSD1 in white adipose tissue
    • converts inactive costerone to active glucocorticoids. thus contribute to pool of GC in the body.
    • positve feedback cycle : chronic stress-->adrenal makes GC --> eat more --> more fat --> more GC
    • 11bHSD1 null mice resist cognitive decline with aging.
    • important drug target
• high 11bHSD level can lead to hypertension
  • via renin-angiotensin system activation
  • cardiovascular disease
• so in summary, glucocorticoid elvels cause obesity, diabetes, heart disease, mood disorder, memory impairment, etc