Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic–pituitary–adrenal axis

Figures & data

Figure 1.  Cellular mechanisms of rapid corticosteroid feedback modulation of principal neurons in the hypothalamus, hippocampus, and amygdala involved in the stress regulatory circuit. The main neuroendocrine branch of the stress response is characterized by CRH release from PVN neuroendocrine cells in the hypothalamus, which stimulates ACTH release from the anterior lobe of the pituitary, which leads to corticosteroid secretion from the adrenal glands into the systemic circulation. The circulating corticosteroid feeds back onto several target structures in the brain, including the hypothalamic PVN, hippocampus, and amygdala, as well as onto the pituitary. The CRH neurons (and oxytocin [OT] and vasopressin [VP] neurons) in the PVN respond rapidly to glucocorticoids with retrograde endocannabinoid (eCB) release and CB1-mediated suppression of glutamate release (Glu) from presynaptic excitatory synapses (Di et al. 2003). Magnocellular OT and VP neurons also release nitric oxide (NO) in rapid response to glucocorticoids, which facilitates GABA release at inhibitory synapses (Di et al. 2009). The CORTs in the hippocampus elicit a presynaptic facilitation of glutamate release from excitatory synapses onto CA1 pyramidal neurons (Karst et al. 2005) and a retrograde NO release that triggers a spike-dependent increase in GABA release from inhibitory synapses onto CA1 neurons (Hu et al. 2010). In the BLA, corticosteroids elicit a rapid increase in glutamate release onto BLA neurons that lack a recent exposure to corticosteroid (unprimed) or a rapid suppression of glutamate release mediated by retrograde endocannabinoids in BLA neurons that have experienced a recent exposure to corticosteroid (primed) (Karst et al. 2010).

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