M10 HPA axis and chronic stress

Topic

The hypothalamic-pituitary-adrenal (HPA) axis coordinates the systemic physiological response to stress through a sequential hormonal cascade: stress triggers the hypothalamus to release corticotropin-releasing hormone, which initiates the entire HPA axis cascade.

This corticotropin-releasing hormone, in turn, stimulates the pituitary gland to secrete a second hormone—adrenocorticotropic hormone; the more adrenocorticotropic hormone the pituitary secretes, the greater the cortisol secretion it induces in the adrenal cortex, thereby extending the cortisol dynamics previously introduced in the major depression model.

This circulating cortisol exerts negative feedback on the hypothalamus and pituitary: higher levels of circulating cortisol result in greater inhibition of corticotropin-releasing hormone and adrenocorticotropic hormone release, thus closing the regulatory loop the HPA axis uses to maintain its activity within a stable range.

However, when HPA axis activation is repeated and sustained over time due to chronic stress, this repeated activation generates an accumulated allostatic load; the greater the accumulated allostatic load, the more the negative feedback mechanism—which previously kept the circuit regulated—becomes desensitized, creating a situation where this desensitization, in turn, perpetuates the dysregulation of the HPA axis. This chronic dysregulation of the hypothalamic-pituitary-adrenal axis has cross-effects on two other processes: on the one hand, it promotes the sustained microglial neuroinflammation previously described in another model in this catalog; on the other, persistently elevated cortisol exerts a direct toxic effect on the hippocampal neuronal population, impairing neurogenesis—a process compounded by the suppression of brain-derived neurotrophic factor, as previously described in the major depression model. Ultimately, it is this hypothalamic-pituitary-adrenal axis—with its sequential hormonal cascade (corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol), its regulatory negative feedback, and the desensitization of that feedback under accumulated allostatic load—that determines whether the stress response remains regulated or becomes chronic, ultimately damaging hippocampal neurogenesis and promoting neuroinflammation.

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