Multisensory Logic of Infant-Directed Aggression by Males

Isogai, Yoh; Zheng, Wu; Love, Michael I.; Ahn, Michael Ho-Young; Bambah-Mukku, Dhananjay; Hua, Vivian; Farrell, Karolina; Dulac, Catherine

doi:10.1016/j.cell.2018.11.032

Cited by 87 publications

(99 citation statements)

References 34 publications

(83 reference statements)

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“…Initially considered a pathological behaviour, pioneering work in langurs and other mammals instead suggested that infanticide is an adaptive behaviour that enables males to gain advantage over rivals and females to adapt reproduction to adverse circumstances 1,2 . Although a number of brain areas have been described as negatively affecting parental behaviour [35][36][37][38][39][40] , the existence of a dedicated control hub for infant-directed agonistic interactions, including infanticide, had not yet been explored.…”

Section: Resultsmentioning

confidence: 99%

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

Autry

Zheng

Kapoor

et al. 2019

Preprint

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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...

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Section: Resultsmentioning

confidence: 99%

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

Autry

Zheng

Kapoor

et al. 2019

Preprint

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“…Interestingly, the non-orthologous receptors are largely clustered in one sub-clade, suggesting different rates of receptor evolution exist within clade C ( Figure 5B ). Two clade C receptors, Vmn1r9 and Vmn1r10 , have been implicated in pup odor detection in house mice (Isogai et al, 2018). However, these receptors also respond to female odors, and thus may detect chemosensory components of the nest environment (Isogai et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Two clade C receptors, Vmn1r9 and Vmn1r10 , have been implicated in pup odor detection in house mice (Isogai et al, 2018). However, these receptors also respond to female odors, and thus may detect chemosensory components of the nest environment (Isogai et al, 2018). These two receptors are part of a single receptor orthogroup ( Vmn1r9/10 ) that is both orthologous and highly duplicated ( Figure 5B ).…”

Section: Resultsmentioning

confidence: 99%

Distinct evolutionary trajectories of V1R clades across mouse species

Miller

Sheehan

Campbell

2019

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29Background: Many animals rely heavily on olfaction to navigate their environment. Among rodents, 30 olfaction is crucial for a wide range of social behaviors. The vomeronasal olfactory system in particular 31 plays an important role in mediating social communication, including the detection of pheromones and 32 recognition signals. Currently, very few vomeronasal receptors have known ligands, which severely limits 33 our understanding of chemosensory-driven social communication. In this study we examine patterns of 34 vomeronasal type-1 receptor (V1R) evolution in the house mouse and related species within the genus 35 Mus. By exploring the evolution of these receptors, we provide insight into the functional roles of receptor 36 subtypes as well as the dynamics of gene family evolution. 37Results: We generated transcriptomes from the vomeronasal organs of 5 Mus species, and produced 38 high quality V1R repertoires for each species. We find that V1R clades in the house mouse and relatives 39 exhibit distinct evolutionary trajectories. Some clades are highly conserved, while others reveal patterns 40 of rapid evolutionary change. We identify putative species-specific gene expansions, including a dramatic 41 clade D expansion in the house mouse. While gene gains are abundant, we detect very few gene losses. 42We describe a novel V1R clade and highlight candidate receptors for future de-orphanization. Based on 43 clade-level evolutionary patterns, we identify receptor families that are strong candidates for detecting 44 social signals and predator cues. Our results further support the view that V1Rs are important for 45 detecting the physiological status of conspecifics, particularly female estrus cues. 46Conclusion: Analysis of clade-level evolution is critical for understanding species' chemosensory 47 adaptations. This study provides clear evidence that V1R clades are characterized by distinct 48 evolutionary trajectories. As receptor evolution is shaped by ligand identity, these results provide a

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“…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).…”

Section: Introductionmentioning

confidence: 99%

A Substantia Innominata-midbrain Circuit Controls a General Aggressive Response

Zhu

Yang

et al. 2020

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SUMMARYAnimals display various aggressive behaviors essential for survival, while ‘uncontrollable’ attacks and abnormal aggressive states have massive social costs. Neural circuits regulating specific forms of aggression under defined conditions have been described, but whether there are circuits governing a general aggressive state to promote diverse aggressive behaviors remains unknown. Here, we found that posterior substantia innominata (pSI) neurons responded to multiple aggression-provoking cues with graded activity of differential dynamics, predicting the aggressive state and the topography of aggression in mice. Activation of pSI neurons projecting to the periaqueductal gray (PAG) increased aggressive arousal and robustly initiated/promoted all the types of aggressive behavior examined in an activity level-dependent manner. Inactivation of the pSI circuit largely blocked diverse aggressive behaviors, but not mating. By encoding a general aggressive state, the pSI-PAG circuit universally drives multiple aggressive behaviors and thus may provide a potential target for alleviating human pathological aggression.

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Multisensory Logic of Infant-Directed Aggression by Males

Cited by 87 publications

References 34 publications

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

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

Distinct evolutionary trajectories of V1R clades across mouse species

A Substantia Innominata-midbrain Circuit Controls a General Aggressive Response

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