HPA axis Flashcards
HPA dysfunction
The hypothalamic-pituitary-adrenal axis is normally activated by stress stimulus and turned off by negative feedback from cortisol.
Function is impaired in certain conditions
Around 50% of depressed patients display HPA hyperactivation.
There is increased cortisol in the saliva, plasma and urine, and increased CRH in the CSF and in limbic brain regions → impaired negative feedback
There’s also an increased size and activity of pituitary and adrenal glands.
CRH, ACTH and cortisol levels change with the circadian rhythm → cortisol peaks in the morning.
Adrenal glands
The outermost layer of the adrenal gland is called the capsule.
The adrenal cortex, consisting of the zona glomerulosa, zona fasciculata and zona reticularis, produces glucocorticoids, such as cortisol, and mineralocorticoids, such as aldosterone.
In the adrenal medulla, chromaffin cells produce catecholamines, such as noradrenaline and adrenaline, which are released into the blood.
Under dual autonomic and endocrine control → the hypothalamus is activated by acute stress, which eventually activates the adrenal glands, and the intermediolateral horn (IML) of the spinal cord targets the SNS and also activates the adrenal glands.
Cortisol increases energy metabolism, lipolysis, protein breakdown, glycogenesis and immunosuppression.
Adrenaline and noradrenaline increase HR, BP, bronchodilation and blood flow to skeletal muscle.
Circadian and episodic control of the adrenal gland
The suprachiasmatic nucleus (SCN) is the central pacemaker of the circadian rhythm. It changes HPA activity depending on signals it receives about light levels.
The SCN can directly activate the adrenal glands.
Cortisol levels peak in the morning, ready for the metabolic demands of the day. This has a direct effect on HR and BP. Cortisol then drops off during the day and thoughts in the evening, readying the body for sleep.
Expression of clock genes has an effect on the circadian rhythm and HPA activation. Mutating clock genes causes a delay in the cortisol level rise. The rhythm is now a response to activity rather than a preparation for activity.
There are also short-term episodic bursts of cortisol during the day. The pulsatile nature allows cells to recover and bursts facilitate the regulation of glutamate transmission and hippocampal LTP.
Stress release of cortisol is independent of circadian changes.
Adaptive value of acute stress
In the short term, the stress response is beneficial, helping improve survival, increase attention, and has physiological benefits.
However, in the long term, these same mechanisms are harmful.
Mineralocorticoid receptors are mainly limbic. They have a high affinity and are therefore occupied by low basal circulating levels of cortisol.
Glucocorticoid receptors are widespread. They have low affinity and are therefore occupied by high circadian/stress levels of cortisol.
The MR receptor is cytosolic and works to alter gene expression.
GR receptors are both membrane bound and cytosolic.
Receptors are widespread throughout the brain, but particularly in the hypothalamus (negative feedback), lateral septum and hippocampus (learning and memory).
There is also a high level of expression of MR in the brainstem. These are related to the nucleus Locus Coeruleus, involved in the stress response.
Locus coeruleus
Noradrenergic neurons primarily originate in the locus coeruleus, which has a high expression of MR, and project to widespread brain areas.
The locus coeruleus plays a role in ageing and Alzheimer’s disease, degenerating during these processes.
Stress causes an increase in activity and excitability in neurons originating in the LC. Over-activation promotes degeneration.
Chronically low levels of cortisol lead to Addison’s disease.
Chronically high levels lead to chronic stress and neurodegeneration.
Locus coeruleus and Alzheimer’s
Amyloid precursor protein (APP) may be internalised following periods of prolonged LC stimulation, allowing APP to act as a substrate for β- and γ-secretases in the endosome.
β2-ARs may interact with the β-arrestin 2 protein that directly interacts with the α-1A subunit of γ-secretase, increasing its catalytic activity.
Over-activation of the LC therefore causes proteolytic activation and accumulation of β-amyloid, which is involved in the development of Alzheimer’s disease.
Prolonged activation of the LC is implicated in dysfunction of neuroinflammation signalling. Microglia adrenergic receptor activation feeds into the cascade of inflammation and neurodegeneration.
