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

Compared to males, aggression is less frequently noticed in females. Fierce maternal-aggression to thwart the attack/threat of 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 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 the rats. Males/dams actively attacked the intruder; virgin-females did not. The dams/males without intruder showed isolated cFos-cells in PMv, but intruder's presence triggered cFos-activation in different PMv-subdivisions in dams/males. Compared to dams without intruder, confrontation with intruder robustly activated PMv^CART-neurons, augmented CART-ir in ventral-PMv and <i>cart</i>-mRNA in PMv-containing tissues in dams. Conversely, in males, 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 ventrolateral-ventromedial hypothalamus (VMHvl) and medial-preoptic nucleus (MPN), we test whether CART-signalling 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 engagement of vPMv and lPMv during maternal and inter-male aggression, respectively, and CART as a key mediator in PMv-VMHvl-pathway to express maternal-aggression in rats.<b>Significance statement</b> Pregnant/lactating rat transiently become fiercely aggressive to protect her pups when challenged by an intruder. The neural mechanism underlying this transitory expression of aggressive behavior is not clear. We identify the role of neuropeptide CART-containing neurons in the hypothalamic premammillary nucleus (PMv) in dams that gives her the behavioral flexibility to display maternal-aggression. A subset of PMv^CART neurons in dams shows dramatic activation when provoked by an intruder while silencing of these neurons suppressed maternal- but not male-male aggression. Further, CART signals the ventrolateral part of the ventromedial hypothalamus to trigger aggression in dams. The study shows CART as a novel messenger in aggression circuitry and PMv^CART a key regulator of maternal-aggression.