Mammals invest considerable resources in protecting and nurturing young offspring. However, under certain physiological and environmental conditions, animals neglect or attack young conspecifics. Males in some species attack unfamiliar infants to gain reproductive advantage [1][2][3] and females kill or neglect their young during stressful circumstances such as food shortage or threat of predation 4-8 . In humans, stress is a risk factor in both sexes for peripartum disorders and associated impairments in parent-infant interactions 9 . While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting 10-13 , the regulation of infantdirected neglect and aggression and the relationship between these behaviours and stress are poorly understood. Here we show that urocortin-3 (Ucn3)-expressing neurons in the perifornical area (PeFA Ucn3 ) of the hypothalamus are activated during infant-directed attacks in males and females, but not other forms of aggression. Opto-and chemogenetic manipulations of PeFA Ucn3 neurons demonstrate the role of this neuronal population in the negative control of parenting in both males and females. PeFA Ucn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send major projections to the ventromedial hypothalamus (VMH), ventral lateral septum (LSv) and amygdalohippocampal area (AHi). Optogenetic activation of PeFA Ucn3 axon terminals in these regions triggers different aspects of infant-directed agonistic responses, such as neglect and aggression. Thus, PeFA Ucn3 neurons emerge as a critical hub for the expression of infant-directed neglect and aggression, providing a new framework to examine the positive and negative regulation of parenting.
RESULTS
Urocortin-3 expressing cells in the perifornical area are specifically activated during infant-directed aggressionTo identify brain areas involved in infant-directed aggression, we monitored the induction of the immediate early gene (IEG) c-fos across the hypothalamus and septal and amygdaloid nuclei in 3 infanticidal virgin males, fathers, and mothers after interactions with pups ( Fig. 1a-b).Significantly more c-fos positive cells were found in the medial bed nucleus of stria terminalis (BNSTm), the LSv, and PeFA of infanticidal males compared to mothers and fathers, with the most robust differences observed in the PeFA, a small nucleus between the fornix and the paraventricular hypothalamus (PVH) (Fig. 1a, b). By contrast, fewer c-fos positive cells were observed in the medial preoptic area (MPOA) of infanticidal males compared to mothers, as expected from previous studies 13,14 (Fig. 1a, b). To identify markers of PeFA cells activated by infant-directed attacks, we visualized c-fos expression in tissue sections from virgin males after interactions with pups and performed microdissections of the corresponding areas in adjacent sections followed by gene expression analysis of the micro-dissected material (Fig. 1c).Expression analysis (see Methods) revealed 26...