Variations in circulating Corticosterone (Cort) are driven by the Paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via CRH targeting the adenohypophysis to release ACTH. Cort feeds back through glucocorticoid receptors (GR). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GR, leaving the question how the ANS in the PVN gets information about circulating Cort to control the adrenal. Since the arcuate nucleus (ARC) shows less restrictive blood brain barrier, expresses GR and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with type II antagonist. At the circadian peak of Cort (afternoon), type II GR antagonist but not type I antagonist increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on conditions as stress or time of the day.
Significance Statement Corticosterone secretion is importantly driven by preautonomic sympathetic neurons in the PVN, while negative feedback of glucocorticoids is generally expected to be mediated via the interaction of CRH neurons in the PVN and corticotrophs in the hypophysis. Here, we demonstrate that the arcuate nucleus rapidly senses circulating Cort and thus adjusts the endocrine adrenal output via the preautonomic neurons in the PVN. This fast control may be an alternative mechanism used by circulating hormones and metabolites to communicate with control centers in the brain via the arcuate nucleus for fast feedback.
Authors report no conflict of interest.
This work was supported by PAPiiT IG200314 and Conacyt 220598