Urocortin III, mouse

Urocortin is a member of the corticotropin-releasing hormone (CRH) family of peptides. In the brain, its potent suppression of food intake is mediated by CRH receptors (CRHR). Urocortin also participates in the regulation of anxiety, learning, memory, and body temperature, and it shows neuroprotection. This review will summarize the location of urocortin-producing neurons and their projections, the pharmacological evidence of its actions in the CNS, and information acquired from knockout mice. Urocortin interacts with leptin, neuropeptide Y, orexin, and corticotropin in the brain. Also produced by the GI tract, heart, and immune cells, urocortin has blood concentrations ranging from 13 to 152 pg/ml. Blood-borne urocortin stimulates the cerebral endothelial cells composing the blood-brain barrier and crosses the blood-brain barrier by a unique transport system. Overall, urocortin acts on a broad neuronal substrate as a neuromodulator important for basic survival.

While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting, the regulation of infant-directed aggression and how it relates to adult-adult aggression is poorly understood. Here we show that urocortin-3 (Ucn3)-expressing neurons in the hypothalamic perifornical area (PeFAUcn3) are activated during infant-directed attacks in males and females, but not other behaviors. Functional manipulations of PeFAUcn3 neurons demonstrate the role of this population in the negative control of parenting in both sexes. PeFAUcn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send projections to hypothalamic and limbic areas. Optogenetic activation of PeFAUcn3 axon terminals in these regions triggers various aspects of infant-directed agonistic responses, such as neglect, repulsion, and aggression. Thus, PeFAUcn3 neurons emerge as a dedicated circuit component controlling infant-directed neglect and aggression, providing a new framework to understand the positive and negative regulation of parenting in health and disease.

Lightly stroking the lips or gently poking some skin regions can evoke mechanical itch in healthy human subjects. Sensitization of mechanical itch and persistent spontaneous itch are intractable symptoms in chronic itch patients. However, the underlying neural circuits are not well defined. We identified a subpopulation of excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) in the dorsal spinal cord as a central node in the pathway that transmits acute mechanical itch and mechanical itch sensitization as well as persistent spontaneous itch under chronic itch conditions. This population receives peripheral inputs from Toll-like receptor 5-positive (TLR5+) Aβ low-threshold mechanoreceptors and is directly innervated by inhibitory interneurons expressing neuropeptide Y::Cre (NPY+) in the dorsal spinal cord. Reduced synaptic inhibition and increased intrinsic excitability of Ucn3+ neurons lead to chronic itch sensitization. Our study sheds new light on the neural basis of chronic itch and unveils novel avenues for developing mechanism-specific therapeutic advancements.