Monday, March 26, 2012

Stress and glucocorticoids in the periphery and CNS

1Glucocorticoid¶

• increase neuronal branches on hippocampal granule neurons
• increase long-term potentiation in the hippocampal CA1
  • illustrated when aldosteron was used as MR agonist
  • opposite effect when RU28362 is an agonist of GR
  • this shows that GC is important for potentiation (memory formation) at low level, when occupied receptors are mostly MR
  • at very high level GC, GR started to get occupied and that leads the opposite effect. (inhibition) neuronal loss
    • also illustrate self-regulatory mechanism since high level of GC leads to inhibition via GR.
• glucocorticoids can exaccerbate neuronal damage caused by excitatory amino acid (glutamate)
  • damage is done through NMDA receptor (which glutamate binds to)
  • APV, a NMDA receptor antagonist, can prevent the damage.

1.1preventions of negative impact of high GC level¶

• patients at the event of stroke often has high glucocorticoid, which leads to neuronal damage.
• Gene delivery approaches:
  • overexpress 1BHSD2: turn corticosterone into 11-dehydro-corticosterone (inactive)
  • transfect cells with inactive GRb : receptor for corticosterone that does nothing.
  • divert functions by using fusion of estrogen receptor (which binds DNA) and GR (binds GC) so instead of glucocorticoid action we have estrogen action on the gene level.
    • transcription of BDNF (neuroprotective brain-derived neurotrophic factor), decreases cell death among CA3 neurons.
  • expression of BDNF: brain-derived neurotrophic factor. decrease cell death in presence of kainic acid and corticosterone.

1.2Diuranl glucocorticoid secretion¶

• important for metabolic regulation
  • at low glucocorticoid: more food intake, protein synthesis, glycogen storage, substarate storage, anabolic
  • at high glucocorticoid:
    • down protein synthesis, insulin, glucose uptake
    • up: glucogenogensis (could lead to diabete), lipolysis, protein breakdown - catabolic

1.3Regulatory Enzymes¶

• 11BHSD1: reactivate inert cortisone to cortisol
  • liver, adipose tissue, lung, macrophage, vascular tissue, CNS
  • high in visceral adipose tissue and some brain regions:
    • so visceral fat is dangerous. fat people can easily get diabete.
    • subcutaneous fat doesn't do that.
• 11BH2D2
  • in kidney, colon, salivary gland, placenta, mid-gestation fetus
  • inactivate glucocoritcoid to inert cortisone.

2Time course of events after stressor¶

• rapid changes through catecholamine (E and NE), CRH/VP, corticosterone (via MR)
• homeostatsis: three scenarios
  • stress response rapidly abolishes the stressor
  • stress response slowly removes the stressor (prolonged acitvation of negative feedback)
  • stress response cannot remove the stressor -- allostatic load (wikipedia: the physiological consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress.)
• different stressor can elicits different pathway, time of onset, peak and magnitude of the response.
  • GC lags behind ACTH amplitude and prolongs after ACTH level has dropped.

3Pathway of stress response¶

• three major signal pathways:
  • top down regulation: stress signals (experience or innate programs) --> limbic forebrain -->BST (bed nucleus of the stria terminalis) and hypothalamus --> HPA activation(PVN)
  • middle management: ongoing hemostatic feedback --> BST and hypothalamus --> PVN
  • stress response triggers : stress signals (homeostatic imbalance, pain, inflammation) --> brainstem, hypothalamus --> PVN
• brain stem and arcuate nucleus directly project to PVN
  • remember the lecture of food intake (NPY and POMC neurons in arcuate nucleus)
• dorsal intrahypothalamus can send stimulation or inhibitory signal to PVN.
• BST: same as above, both stimulating or inhibitory signal to PVN.
• mediopreoptic is inhibitory ot PVN and it stimulates GnRH release

• prefrontal cortex:

  • ventral prefrontal cortex (PFC) (or prelimbic) is inhibitory to CRF neurons in PVN:
    • lesion of ventral PFC in addition to stress lead to high expression fo CRF.
    • act via release of GABA on CRF neurons in PVN.
  • dorsal prefrontal cortex (or infralimbic)is excitatory to PVN
    • higher ACTH when dorsal PFC is stimulated.
    • act via BST which projects to and stimulates PVN.

• CRH expression

  • remember that immediate and transient expression is shown by CRH hnRNA (which gets converted to mRNA later)
  • longer response is indicated by mRNA expression
  • upon injection of LPS, there's a difference between CRH hnRNA expression (you have less CRF hnRNA ?)
    • effect of LPS on CRF expression is not so obvious by just looking at mRNA

3.1Limbic output¶

• hippocampus : memory related, site of negative GC feedback
  • directly inhibit PVN by releasing GABA
• amygdala: emotion, indirect projection to PVN
  • project to BST which then relays to PVN.
• prefrontal cortex (as mentioned before)
  • infralimbic : excitatory to PVN
  • prelimbic : inhibitory to PVN
• (so the same nuclei can have opposite effect on PVN)

4Stress response and factors¶

• stress responsiveness varies as a function of the phase of ultradian corticosterone rhythm.
  • stress during falling phase -> less neuronal activation in amygdala and less ACTH surge
  • stress during rising phase -> ACTH surge, neuraonl activation in amydgala increases
• we can induce pulses of GC by injecting GC periodically and look at GR internalization into the nucleus
  • in liver : peak of GC is followed by PER1 level (a clock gene)
• stress test (gender):
  • done by measuring salivary GC (free, biologically active GC)
  • male has higher ACTH level : stronger response to stress
  • but female has higher cortisol level
    • maybe cuz females' adrenal glands are more sensitive to ACTH.
• stress test (age) :
  • young men have higher ACTH than old men but lower cortisol level than old men
  • old people have sluggish negative feedback.
    • lower ACTH but high glucocorticoid comparing to those in the same gender group but younger age
      • due to strong negative feedback on ACTH production but delayed response
    • if GC level is too high, would lead to cognitive function impairement)
  • although older people have only a slightly higher glucocorticoid level at any given time, accumulated effect is detrimental.
• social factor:
  • children with family have normal cortisol cycle
  • children of orphanage have blunted cortisol level : tonically elevated GC
    • also seen in chronically stressed individuals.
• illness:
  • in almost all cases, people with illness have higher glucocorticoid level.