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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.
- ventral prefrontal cortex (PFC) (or prelimbic) is inhibitory to CRF neurons in 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)
- lower ACTH but high glucocorticoid comparing to those in the same gender group but younger age
- 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.