Estrogen Control of Social Behaviors.

Social behaviors, including parental care, mating, and fighting, all depend on the hormonal milieu of an organism. Decades of work highlighted estrogen as a key hormonal controller of social behaviors, exerting its influence primarily through binding to estrogen receptor alpha (Esr1). Recent technological advances in chemogenetics, optogenetics, gene editing, and transgenic model organisms have allowed for a detailed understanding of the neuronal subpopulations and circuits for estrogen action across Esr1-expressing interconnected brain regions.

Experience-dependent dopamine modulation of male aggression.

Numerous studies support the role of dopamine in modulating aggression, but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors.

Stress and parental behaviors.

In nearly all mammalian species, newborn pups are weak and vulnerable, relying heavily on care and protection from parents for survival. Thus, developmentally hardwired neural circuits are in place to ensure the timely expression of parental behaviors. Furthermore, several neurochemical systems, including estrogen, oxytocin, and dopamine, facilitate the emergence and expression of parental behaviors.

Leptin-activated hypothalamic BNC2 neurons acutely suppress food intake.

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons. However, whereas AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect.

The multi-stage plasticity in the aggression circuit underlying the winner effect.

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the "winner effect." Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice. This behavioral change is supported by three causally linked plasticity events in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression.

The multi-stage plasticity in the aggression circuit underlying the winner effect.

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the "winner effect". Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice, which is supported by three stages of plasticity in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10-day winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, a transient local connectivity strengthening, and a delayed excitability increase.

Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network.

Distributed hypothalamic-midbrain neural circuits help orchestrate complex behavioral responses during social interactions. Given rapid advances in optical imaging, it is a fundamental question how population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. This paper aims to investigate the correspondence between MFP data and social behaviors.

Monitoring norepinephrine release in vivo using next-generation GRAB sensors.

Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter. The first-generation NE sensor makes in vivo, real-time, cell-type-specific and region-specific NE detection possible, but its low NE sensitivity limits its utility. Here, we developed the second-generation GPCR-activation-based NE sensors (GRAB and GRAB) with a superior response and high sensitivity and selectivity to NE both in vitro and in vivo.

Brain-wide multi-fiber recording of neuronal activity in freely moving mice.

While brain regions function in coordination to mediate diverse behaviors, techniques allowing simultaneous monitoring of many deep brain regions remain limited. Here, we present a multi-fiber recording protocol that enables simultaneous recording of fluorescence signals from multiple brain regions in freely behaving mice. We describe steps for assembling a multi-fiber array and patch cord, implantation, and recording.

Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network.

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).

A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors.

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.

Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors.

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) are specialized for processing male conspecific cues and are essential for adult inter-male aggression.

Hypothalamic control of innate social behaviors.

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.

Neural dynamics in the limbic system during male 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 Ca signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting.

Antagonistic circuits mediating infanticide and maternal care in female mice.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear.

A hypothalamic pathway that suppresses aggression toward superior opponents.

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) to the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential pathway for modulating aggression in male mice. cMPOA cells increase activity mainly during male-male interaction, which differs from the female-biased response pattern of rostral MPOA (rMPOA) cells.

Hardwired to attack: Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors.

Social behaviors are innate and supported by dedicated neural circuits, but it remains unclear whether these circuits are developmentally hardwired or established through social experience. Here, we revealed distinct response patterns and functions in social behavior of medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages. MeA cells in male mice that express the transcription factor Foxp2 (MeA) are specialized for processing male conspecific cues even before puberty and are essential for adult inter-male aggression.

Neural control of female sexual behaviors.

Reproduction is the biological process by which new individuals are produced by their parents. It is the fundamental feature of all known life and is required for the existence of all species. All mammals reproduce sexually, a process that involves the union of two reproductive cells, one from a male and one from a female.

To see is to experience: Aggression neurons light up when witnessing a fight.

Fighting is an intense experience not only for the executors but also for the observers. In the current issue of Cell, Yang et al. identified hypothalamic aggression mirror neurons, activated during both physical fighting and witnessing a fight, possibly representing a neural mechanism for understanding social experiences in other minds.

A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments.

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.

Responses and functions of dopamine in nucleus accumbens core during social behaviors.

Social behaviors are among the most important motivated behaviors. How dopamine (DA), a "reward" signal, releases during social behaviors has been a topic of interest for decades. Here, we use a genetically encoded DA sensor, GRAB, to record DA activity in the nucleus accumbens (NAc) core during various social behaviors in male and female mice.

VMHvll cells dynamically control female sexual behaviors over the reproductive cycle.

Sexual behavior is fundamental for the survival of mammalian species and thus supported by dedicated neural substrates. The ventrolateral part of ventromedial hypothalamus (VMHvl) is an essential locus for controlling female sexual behaviors, but recent studies revealed the molecular complexity and functional heterogeneity of VMHvl cells. Here, we identify the cholecystokinin A receptor (Cckar)-expressing cells in the lateral VMHvl (VMHvll) as the key controllers of female sexual behaviors.

Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators.

Neurotransmitters and neuromodulators have a wide range of key roles throughout the nervous system. However, their dynamics in both health and disease have been challenging to assess, owing to the lack of in vivo tools to track them with high spatiotemporal resolution. Thus, developing a platform that enables minimally invasive, large-scale and long-term monitoring of neurotransmitters and neuromodulators with high sensitivity, high molecular specificity and high spatiotemporal resolution has been essential.