Peripheral ghrelin administration prevents the behavioral effects of restraint stress in mice: possible implication of PVNCRH neurons.

Ghrelin is a gut-derived hormone that is secreted during conditions of negative caloric balance and acts as a key modulator of feeding, increasing food intake and affecting several physiological systems such as metabolism, behavior and the control of endocrine and autonomic functions. Previous studies showed that ghrelin participates in the stress response, acting on hypothalamic paraventricular nucleus neurons that express corticotropin-releasing hormone (PVNCRH neurons). In the present study, we investigated the effects of ghrelin administration on the behavioral responses to restraint stress in mice. In their homecage, C57Bl6 mice in basal conditions expressed the behaviors of surveying, walking, rearing, grooming and, to a lesser extent, digging, climbing and freezing. Restraint stress increased the time spent in grooming without significant changes in other behaviors. Ghrelin administration did not affect behavior in control mice, but it reversed the effect of restraint stress on grooming. Chemogenetic activation of PVNCRH neurons by clozapine N-Oxide (CNO) administration in hM3Dq DREADD mice increased grooming, while ghrelin mitigated this effect. In addition, CNO administration decreased walking and rearing, both in the presence or absence of ghrelin. Food intake was increased by ghrelin administration, however, it was not affected by stress or CNO. These results indicate that ghrelin decreases the activity of PVNCRH neurons, partially preventing the behavioral effects of restraint stress. The inhibitory input to PVNCRH neurons probably arrives from other nuclei, since GABAergic neurons were not identified in the PVN neurons of these mice.