Faculty Bibliography

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks¹. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOR^OXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvl^OXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvl^OXTR cells minimally respond to aggressor cues. During defeat, aVMHvl^OXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvl^OXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.

Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.

Social behaviors are innate and supported by dedicated neural circuits, but the molecular identities of these circuits and how they are established developmentally and shaped by experience remain unclear. Here we show that medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages have distinct response patterns and functions in social behavior in male mice. MeA cells expressing the transcription factor Foxp2 (MeA^Foxp2) are specialized for processing male conspecific cues and are essential for adult inter-male aggression. By contrast, MeA cells derived from the Dbx1 lineage (MeA^Dbx1) respond broadly to social cues, respond strongly during ejaculation and are not essential for male aggression. Furthermore, MeA^Foxp2 and MeA^Dbx1 cells show differential anatomical and functional connectivity. Altogether, our results suggest a developmentally hardwired aggression circuit at the MeA level and a lineage-based circuit organization by which a cell's embryonic transcription factor profile determines its social information representation and behavioral relevance during adulthood.

Neuropeptides are key signaling molecules in the endocrine and nervous systems that regulate many critical physiological processes. Understanding the functions of neuropeptides in vivo requires the ability to monitor their dynamics with high specificity, sensitivity, and spatiotemporal resolution. However, this has been hindered by the lack of direct, sensitive, and noninvasive tools. We developed a series of GRAB (G protein-coupled receptor activation‒based) sensors for detecting somatostatin (SST), corticotropin-releasing factor (CRF), cholecystokinin (CCK), neuropeptide Y (NPY), neurotensin (NTS), and vasoactive intestinal peptide (VIP). These fluorescent sensors, which enable detection of specific neuropeptide binding at nanomolar concentrations, establish a robust tool kit for studying the release, function, and regulation of neuropeptides under both physiological and pathophysiological conditions.

Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.

Sexual, parental, and aggressive behaviors are central to the reproductive success of individuals and species survival and thus are supported by hardwired neural circuits. The reproductive behavior control column (RBCC), which comprises the medial preoptic nucleus (MPN), the ventrolateral part of the ventromedial hypothalamus (VMHvl), and the ventral premammillary nucleus (PMv), is essential for all social behaviors. The RBCC integrates diverse hormonal and metabolic cues and adjusts an animal's physical activity, hence the chance of social encounters. The RBCC further engages the mesolimbic dopamine system to maintain social interest and reinforces cues and actions that are time-locked with social behaviors. We propose that the RBCC and brainstem form a dual-control system for generating moment-to-moment social actions. This Review summarizes recent progress regarding the identities of RBCC cells and their pathways that drive different aspects of social behaviors.

Sexual and aggressive behaviors are vital for species survival and individual reproductive success. Although many limbic regions have been found relevant to these behaviors, how social cues are represented across regions and how the network activity generates each behavior remains elusive. To answer these questions, we utilize multi-fiber photometry (MFP) to simultaneously record Ca²⁺ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting. We find that conspecific sensory information and social action signals are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in the network functional connectivity during the social action initiation phase, whereas late copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRAB_OT1.0. In contrast to previous methods, GRAB_OT1.0 enables imaging of OT release ex vivo and in vivo with suitable sensitivity, specificity and spatiotemporal resolution. Using this sensor, we visualize stimulation-induced OT release from specific neuronal compartments in mouse brain slices and discover that N-type calcium channels predominantly mediate axonal OT release, whereas L-type calcium channels mediate somatodendritic OT release. We identify differences in the fusion machinery of OT release for axon terminals versus somata and dendrites. Finally, we measure OT dynamics in various brain regions in mice during male courtship behavior. Thus, GRAB_OT1.0 provides insights into the role of compartmental OT release in physiological and behavioral functions.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state^1,2. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring^3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits^5,6, we use the medial preoptic area (MPOA), a key site for maternal behaviours^7-11, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTpr^ESR1) are necessary, sufficient and naturally activated during infanticide in female mice. MPOA^ESR1 and BNSTpr^ESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOA^ESR1 and BNSTpr^ESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.

Aggression is costly and requires tight regulation. Here we identify the projection from estrogen receptor alpha-expressing cells in the caudal part of the medial preoptic area (cMPOA^Esr1) to the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential pathway for modulating aggression in male mice. cMPOA^Esr1 cells increase activity mainly during male-male interaction, which differs from the female-biased response pattern of rostral MPOA^Esr1 (rMPOA^Esr1) cells. Notably, cMPOA^Esr1 cell responses to male opponents correlated with the opponents' fighting capability, which mice could estimate based on physical traits or learn through physical combats. Inactivating the cMPOA^Esr1-VMHvl pathway increased aggression, whereas activating the pathway suppressed natural intermale aggression. Thus, cMPOA^Esr1 is a key population for encoding opponents' fighting capability-information that could be used to prevent animals from engaging in disadvantageous conflicts with superior opponents by suppressing the activity of VMHvl cells essential for attack behaviors.