Identification of urocortin 3 afferent projection to the ventromedial nucleus of the hypothalamus in rat brain

Urocortin 3 (Ucn 3) is a corticotrophin-releasing factor related neuropeptide highly expressed in the brain. Ucn 3 nerve fibers heavily innervate the hypothalamic ventromedial nucleus (VMH), and Ucn 3 injection into the VMH suppresses feeding. Currently, the origin of the Ucn 3 afferent input into the VMH is unknown. In the present study, anatomical tracing shows that the major Ucn 3 afferent input to the VMH resides in the anterior parvicellular part of the paraventricular nucleus of the hypothalamus (PVHap) and the adjacent posterior part of the bed nucleus of stria terminalis (pBNST). VMH also receives moderate Ucn 3 input from the medial amygdala. Ucn 3 neurons located immediately caudal to the PVHap/pBNST in the rostral perifornical hypothalamic area (rPFH) provide only minimal input. The paucity of rPFH-VMH Ucn 3 projection is consistent with the finding that only Ucn 3 neurons in the rPFH co-expressed enkephalin (Enk), and Ucn 3/Enk double-labeled nerve fibers and terminals were observed predominately in the lateral septum (LS), whereas only a few double-labeled fibers were found in other brain areas including the VMH. Furthermore, retrograde tracing demonstrates that Ucn 3 neurons in the rPFH project to the LS. In conclusion, the present study determines that the major Ucn 3 afferent into the VMH originates from the PVHap/pBNST. Moreover, anatomical heterogeneity is observed in the hypothalamic Ucn 3 neuron population as the rostral part (PVHap/pBNST) of the population projects to the VMH and the caudal part (rPFH) co-localizes with Enk and provides major afferent input to the LS.