HPA Axis Flashcards
Is the response to stress all about the hypothalamus?
Nope. Higher cortical areas are involved in determining that the individual is somehow threatened and should be stressed.
Two main systems for responding to stress? Which is fast, which is slow?
Sympathetic nervous system - fast
HPA axis - slow
MCAT review: What’s the basic pathway from hypothalamus to cortisol?
Hypothal makes CRF –> CRF stimulates ant. pituitary to make ACTH –> ACTH stim adrenal medulla to make glucocorticoids.
For a single point-like bolus of stress, when does the cortisol response peak?
At 30 minutes.
What’s one way that glucocorticoid negative feedback occurs?
Inhibition of of CRF release from the hypothalamus.
Review: What’s the primary glucocorticoid?
Cortisol
To what receptors does cortisol bind?
GR (glucocorticoid receptor) and MR (mineralocorticoid receptor).
Note that cortisol actually binds MR better than does aldosterone.
How can cortisol be prevented from binding to MR?
It can be converted to cortisone by 11-beta-hydroxysteroid dehydrogenases
What are 2 synthetic GR agonists?
1 synthetic MR agonists?
GR: dexamethasone and prednisone
MR: Spironolactone
Does cortisol normally cross the placenta?
No, it is usually converted to cortisone, but this can be overwhelmed when there’s a lot of maternal stress.
What has higher affinity for glucocorticoids, MR or GR? How does this relate to their roles?
MR - high affinity, for maintaining “basal HPA tone”
GR - low affinity, responsible for neg. feedback
Review: What kind of receptor is GR? Give a brief description of how it works.
Cytosolic receptor is sequested (by HSPs) in the cytosol until it is bound by ligand. When the ligand binds, GR translocates to the nucleus and acts as a transcription factor.
(note that this mechanism inadequately explains how rapidly cortisol acts)
Review: How does cortisol relate to circadian rhythms?
It peaks, on average, at about 7-8am - which is a socially acceptable time to wake up.
How do people’s aldosterone, renin, and cortisone adjust to circadian shifts (i.e. night shift work)?
Adolesterone and renin adjust, but cortisol does not. It keeps peaking at 7-8am.
What effect do exogenous glucocorticoids such as prednisone have on cortisol?
These suppress endogenous glucocorticoid release via negative feedback. (secondary adrenal insufficiency - why you must taper patients off prednisone)
5 mental disorders that can be caused by prednisone?
Depression Delirium Panic Paranoia Mania/hypomania
What are the acute “survival-promoting” effects caused by glucocorticoids? (2 main things)
Increase glucose availability (from fat, glycogen, proteins,decreasing insulin sensitivity).
Promotes emotional and habitual (i.e. implicit) memory and cognition (while diminishing declarative and episodic memory).
What are 3 “non-essential” systems inhibited by glucocorticoids?
Immune and inflammatory reactions.
Pituitary gonadotropin release / sensitivity of target tissues to them.
Osteoblast activity, leading to decreased bone mass.
What are the pathological effects of stress on memory? Areas of brain affected? How can this be visualized?
Less hippocampal, episodic memory.
More amygdala, emotional memory. (eg. PTSD).
This can actually be seen in the degree of “arborization” in these areas (decreased in hippocampus, increased in amygdala)
What mediates the effects of chronic stress?
“glucocorticoid reprogramming” e.g. reorganizing the brain toward threat assessment.
How are cortisol levels in PTSD and depression vs. controls?
Cortisol is lower in PTSD (esp at waking), higher in depression.
What does the dexamethasone suppression test test? What happens in PTSD?
Normally, it should suppress cortisol production.
In PTSD, dexamethasone “hypersuppresses” cortisol.(we don’t know why, but probably due to increased cortisol receptors)
Does glucocorticoid hyper-release correlate with a good or poor prognosis for depression?
Better for prognosis, unclear why.
How are cortisol levels altered by fatty foods and drugs of abuse?
They lower cortisol. Withdrawal from addictive drugs and fatty foods promotes cortisol level increases.
Where is CRF produced?
Hypothalamus, mainly the median eminence.
Does CRF only act on the anterior pituitary?
No, it has broad activity in the brain.
What are the 3-4 known molecules in the CRF family?
CRF
Urocortin
Urocortin II and III
What are the 2 CRF-receptors, and what are their proposed functions?
CRF-R1 -> pro-stress
CRF-R2 -> recovery from / modulation of stress
What ligands bind CRF-R1?
CRF and urocortin
What ligand bind CRF-2?
Urocortin, and urocortin II and III.
Correlations between CRF and and mental health?
CRF increased in depression.
CRF receptors are downregulated in suicide.
Remember those rats that pass on their mothering habits epigenetically? What is one gene that is methylated differently there?
the GR gene.
