CART Neurons in the Hypothalamic Ventral Premammillary Nucleus (PMv) in Rats Mediate Maternal, But Not Inter-male...

Compared to males, aggression is less frequently noticed in females. Fierce maternal-aggression to thwart the attack/threat of a male conspecific/intruder is transiently expressed as she defends her pups. The odor cues emanated by the intruder provoke aggressive behavior by robustly activating the ventral-premammillary nucleus (PMv) in the hypothalamic-attack area (HAA). But, how PMv activation triggers aggression is unclear. In view of neuropeptide cocaine- and amphetamine-regulated transcript (CART)'s potential to reconfigure neural circuits for behavioral demands, occurrence throughout aggression circuitry, and abundance particularly in PMv, we test the role of PMv^CART in maternal and inter-male aggression in rats. Males/dams actively attacked the intruder; virgin females did not. The dams/males without intruder showed isolated c-Fos cells in PMv, but the intruder's presence triggered c-Fos-activation in different PMv-subdivisions in dams/males. Compared to dams without intruder, confrontation with intruder robustly activated PMv^CART-neurons and augmented CART-ir in ventral-PMv and cart-mRNA in PMv-containing tissues in dams. Conversely, in males, the intruder's presence activated lateral-PMv^CART neurons, but CART-levels remained unaltered. Intra-PMv CART-siRNA administration suppressed maternal-aggression, but male aggression was unaffected. Since PMv is strongly connected with the ventrolateral-ventromedial hypothalamus (VMHvl) and medial preoptic nucleus (MPN), we test whether CART signaling to these nuclei triggers maternal aggression. While VMHvl showed stronger CARTergic-axonal input than MPN, immunoneutralization of CART in VMHvl, but not MPN, blocked maternal-aggression. CART may drive the circuit beyond HAA since VMHvl neurons contacted by CART-axons project to periaqueductal gray. We identify the engagement of vPMv and lPMv during maternal and inter-male aggression, respectively, and CART as a key mediator in the PMv-VMHvl pathway to express maternal-aggression in rats.