Cortisol Pathway

Hormone pathway for cortisol (source)

Both physiological stimuli and stress trigger the HPA axis leading to glucocorticoids (GCs, cortisol in humans) release from the adrenal cortex:

  • Physiological homeostatic challenges involve, through sensory relays, the direct noradrenergic and peptidergic (originating mainly from the nucleus of the solitary tract) stimulation of the corticotrophin-releasing hormone (CRH) neurons which are located in the dorsomedial parvocellular (mp) division of the hypothalamic paraventricular nucleus (PVN) [37]. Further processing of the information includes glutamatergic, serotoninergic, and cytokine stimulation of the PVN. Under specific conditions, GABA can also stimulate the HPA axis at the PVN.
  • Anticipatory responses involve the trans-synaptic activation of the HPA axis through the integration of multimodal sensory information, and the respective higher processing, which involves the ventral hippocampus, the medial prefrontal cortex, and the amygdala, among other limbic structures [7].
  • Hypothalamic PVN is subject to regulation by several structures by way of glutamatergic and GABAergic neurons and the endocannabinoid system.
  • The amygdala plays an important role in the defensive responses to learned threats. [38]. The lateral nucleus is important for the acquisition of aversive learning [39,40]. The aversive stimulus is recognised and processed in the amygdala’s basolateral complex, which connects with the central nucleus to stimulate the brainstem through CRH projections to the locus coeruleus [41] and the hypothalamus preparing the person to cope with the stimulus.
  • GCs act through rapid non-genomic mechanisms in the basolateral amygdala through a membrane GC receptor (mGR), inducing the release of endocannabinoids from postsynaptic membranes, generating a retrograde feedback suppression on GABAergic neurons, and thereby driving the release of norepinephrine to the amygdala, which is required for emotional memory acquisition [42,43]. The prefrontal cortex and the hippocampus project to both the PVN and the amygdala in order to regulate the response to the aversive stimulus [7,44].
  • CRH binds to the CRH type 1 receptor in the anterior pituitary, stimulating the release of the adrenocorticotrophic hormone (ACTH) into the bloodstream. Arginine vasopressin is co-released and it complements CRH actions in ACTH release.
  • ACTH action on the adrenal cortex leads to cortisol production and release, which is potentiated by the sympathetic nervous system and cytokines.
  • The GC response depends on the timing of the stressful event: if this event occurs during the ascending phase of the ultradian pulse, it tends to have a greater level of response than if it were to occur during the falling phase [7,45].
  • Cortisol serves several functions, including mobilisation of energy to cope with the aversive stimuli, memory processing, immune system modulation, the termination of the response by active feedback processes, repressing all unnecessary activity—such as growth (emergency mode: when a person is faced with a traumatic event (TE) GCs inactivate all non-essential activities for survival [46]). Another important effect of GCs is to enhance the consolidation of the memories of fear and other strong emotions to facilitate coping with re-exposure [47].