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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 (PeFA Ucn3 ) are activated during infant-directed attacks in males and females, but not other behaviors. Functional manipulations of PeFA Ucn3 neurons demonstrate the role of this population in the negative control of parenting in both sexes. PeFA Ucn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send projections to hypothalamic and limbic areas. Optogenetic activation of PeFA Ucn3 axon terminals in these regions triggers various aspects of infant-directed agonistic responses, such as neglect, repulsion, and aggression. Thus, PeFA Ucn3 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.

Caregiving behavior is highly conserved in animals, particularly mammals. While the phenotypic expression of caregiving may differ across species, the goal of this behavior is to increase the likelihood of infant survival. In laboratory mice, a range of infant-directed responses can be observed including caregiving, neglect, or infant-directed aggression and attack. However, around 2-3 weeks after mating, these aggressive tendencies decrease, giving way to parental behaviors such as pup retrieval and grooming. This shift offers a valuable framework for studying the neural mechanisms regulating infant care in males and females. We recently found that projections from urocortin-3 (Ucn3) neurons to the posterior amygdala, including the posterodorsal medial amydgala (MePd) and the amygdalohippocampal area (AHi), promoted infant-directed aggression in females. We explore how both amygdala regions influence caregiving and other social behaviors. Regarding the MePd, Ucn3 binds with high affinity to corticotropin releasing factor receptor-2 (CRFR-2), and Ucn3 to CRFR-2 signaling in the MeA has been shown to mediate social preference. We set out to dissect the role of CRFR-2 expressing neurons in the MePd and hypothesized that these neurons would be selectively active during infant-directed aggression in males, and that their activity would promote infant-directed aggression, but not adult aggression, in both sexes. Using fiber photometry recordings, we confirm that infant odors activate MePd CRFR-2 neurons across behavioral states and sex, but these neurons also strongly respond during infant-directed aggression in virgin males. Chemogenetic activation of these neurons elicits infant-directed aggression in virgin males and females as well as mated males, while this effect is blunted in mated females. Anatomical tracing uncovers strong projections of MePd CRFR-2 neurons to the bed nucleus of stria terminalis (BNST), anterior hypothalamus, and posterior lateral hypothalamus. Inhibition of the MePd CRFR-2 projection to the BNST suppresses infant-directed aggression. Altogether, these results reveal a role for MePd CRFR-2 neurons in regulating expression of infant-directed behaviors in both sexes. Pertaining to the AHi, we hypothesize that this region is integral in both sociosexual behaviors as well as metabolic function. To test this hypothesis, we lesioned the AHi using NMDA in males and females. Through lesion studies, we find that total loss of function of the AHi results in increased infant-directed aggression and social dominance in females suggesting that the AHi plays a role in infant- and adult-directed aggressive behavior. Additionally, we observed sexually dimorphic metabolic disruptions such as increased weight gain in females, and hyperphagia in males compared to non-lesioned controls. We believe that these studies provide critical insights into the amygdala’s role in caregiving and other social behaviors.

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.

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 and females kill or neglect their young during stressful circumstances such as food shortage or threat of predation. In humans, stress is a risk factor in both sexes for peripartum disorders and associated impairments in parent-infant interactions. While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting, the regulation of infant-directed 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 (PeFAUcn3) of the hypothalamus are activated during infant-directed attacks in males and females, but not other forms of aggression. Opto- and chemogenetic manipulations of PeFAUcn3 neurons demonstrate the role of this neuronal population in the negative control of parenting in both males and females. PeFAUcn3 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 PeFAUcn3 axon terminals in these regions triggers different aspects of infant-directed agonistic responses, such as neglect and aggression. Thus, PeFAUcn3 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.