Urocortin-3 Neurons in the Mouse Perifornical Area Promote Infant-directed Neglect and Aggression

Abstract

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...

Hypothalamic perifornical Urocortin-3 neurons modulate defensive responses to a potential threat stimulus

“…There is a report demonstrating that PeFA Ucn3 neurons, particularly a rostral population (more rostral than −0.5 mm to the bregma), not caudal, were activated by infant-direct aggression ( Autry et al, 2019 ). Based on the anatomical coordinates, the population of PeFA Ucn3 neurons activated by infant-direct aggression may differ from those activated by a novel object stimulus.…”

“…In the hypothalamus, Ucn3-expressing neurons are found in the median preoptic nucleus and rostral perifornical area (PeFA) lateral to the paraventricular nucleus (PVN) ( Li et al., 2002 ). In rodents, PeFA Ucn3 neurons are considered to mainly project to the ventromedial hypothalamic nucleus (VMH) and the lateral septum (LS) ( Autry et al, 2019 ; Chen et al., 2011 ; Kuperman et al., 2010 ).…”

“…However, differently from CRFR2-mutant mice ( Bale et al., 2000 ; Bale and Vale, 2003 ; Coste et al., 2000 ), Ucn3-deficient mice did not show impairments in hypothalamic-pituitary-adrenal axis regulation and anxiety- or depression-related behaviors ( Deussing et al., 2010 ). Furthermore, a more recent study has reported a different function of PeFA Ucn3 neurons from stress-related responses: the anterior portion of PeFA Ucn3 neurons (−0.1 to −0.5 mm to the bregma) is activated during infant-directed attack, and activation of these neurons elicit infant-directed neglect and aggression ( Autry et al, 2019 ). Nevertheless, there are still no studies investigating the effects of activation and ablation/inhibition of PeFA Ucn3 neurons on anxiety-like behaviors.…”

Brain transcriptomic changes in Japanese quail reveal roles for neurotensin and urocortin 3 in avian parental care

“…One is the poison frog paper mentioned above [22] where urocortin-3 was upregulated in the preotic area of frogs performing parental care relative to non-parental one. The other one revealed that urocortin-3 expressing neurons in the perifornical area of the hypothalamus are activated specifically during infant-directed aggression in both male and female mice and that optogenetic activation of these neurons triggers infantdirected aggression and neglect [29]. Given that we observed a reduction in aggression towards chicks after the sensitization procedure [5], urocortin-3 may have an opposing effect on infant-directed aggressive behaviour in our system or serve different functions that support parental care, such as altered feeding patterns [30,31].…”

A Substantia Innominata-midbrain Circuit Controls a General Aggressive Response

“…Animals exhibit a range of aggressive behaviors (Blanchard et al, 2003; Moyer, 1968) essential for survival, reproduction, and social hierarchy establishment (Nelson and Trainor, 2007), while pathological aggression and the inability to control aggressive states cause serious social problems (Coccaro, 2012; Davidson, 2000; Siegel and Victoroff, 2009). Distinct regions in the mouse brain have been shown to be essential for male (Chamero et al, 2007; Hong et al, 2014; Lee et al, 2014; Leroy et al, 2018; Lin et al, 2011; Stagkourakis et al, 2018; Stowers et al, 2002; Todd et al, 2018; Unger et al, 2015; Yang et al, 2013; Yang et al, 2017; Zelikowsky et al, 2018), female (Hashikawa et al, 2017; Unger et al, 2015), predatory (Han et al, 2017; Li et al, 2018; Park et al, 2018; Shang et al, 2019; Zhao et al, 2019), and infant-directed (Autry et al, 2019; Chen et al, 2019; Isogai et al, 2018; Trouillet et al, 2019) aggressive behaviors. Furthermore, studies from some brain regions that have been examined for more than one type of aggressive behaviors suggest that different behaviors are regulated by distinct, dedicated neural circuits under specific internal and external conditions (Chen and Hong, 2018; Chen et al, 2019; Han et al, 2017; Hashikawa et al, 2017; Isogai et al, 2018; Yang et al, 2017; Zelikowsky et al, 2018).…”