A hypothalamic circuit for circadian regulation of corticosterone secretion

The secretion of cortisol in humans and corticosterone (Cort) in rodents follows a daily rhythm which is important in readying the individual for the daily active cycle and is impaired in chronic depression. This rhythm is orchestrated by the suprachiasmatic nucleus (SCN) which governs the activity of neurons in the paraventricular nucleus of the hypothalamus that produce the corticotropin-releasing hormone (PVH ^CRH neurons). The dorsomedial nucleus of the hypothalamus (DMH) serves as a crucial intermediary, being innervated by the SCN both directly and via relays in the subparaventricular zone, and projecting axons to the PVH, thereby exerting influence over the cortisol/corticosterone rhythm. However, the role and synaptic mechanisms by which DMH neurons regulate the daily rhythm of Cort secretion has not been explored. We found that either ablating or acutely inhibiting the DMH glutamatergic (DMH ^Vglut2 ) neurons resulted in a 40-70% reduction in the daily peak of Cort. Deletion of the Vglut2 gene within the DMH produced a similar effect, highlighting the indispensable role of glutamatergic signaling. Chemogenetic stimulation of DMH ^Vglut2 neurons led to an increase of Cort levels, and optogenetic activation of their terminals in the PVH in hypothalamic slices directly activated PVH ^CRH neurons through glutamate release (the DMH ^Vglut2 → PVH ^CRH pathway). Similarly, ablating, inhibiting, or disrupting GABA transmission by DMH GABAergic (DMH ^Vgat ) neurons diminished the circadian peak of Cort, particularly under constant darkness conditions. Chemogenetic stimulation of DMH ^Vgat neurons increased Cort, although with a lower magnitude compared to DMH ^Vglut2 neuron stimulation, suggesting a role in disinhibiting PVH ^CRH neurons. Supporting this hypothesis, we found that rostral DMH ^Vgat neurons project directly to GABAergic neurons in the caudal ventral part of the PVH and adjacent peri-PVH area (cvPVH), which directly inhibit PVH ^CRH neurons, and that activating the DMH ^Vgat terminals in the cvPVH in brain slices reduced GABAergic afferent input onto the PVH ^CRH neurons. Finally, ablation of cvPVH ^Vgat neurons resulted in increased Cort release at the onset of the active phase, affirming the pivotal role of the DMH ^Vgat → cvPVH ^Vgat → PVH ^CRH pathway in Cort secretion. In summary, our study delineates two parallel pathways transmitting temporal information to PVH ^CRH neurons, collectively orchestrating the daily surge in Cort in anticipation of the active phase. These findings are crucial to understand the neural circuits regulating Cort secretion, shedding light on the mechanisms governing this physiological process and the coordinated interplay between SCN, DMH, and PVH.