Faculty Bibliography

RATIONALE/BACKGROUND:Aggression is an innate social behavior prevalent across animal species. However, in modern human society, inter-personal aggression is considered disruptive and detrimental to both families and communities. Clinically, antipsychotics, which primarily target dopamine (DA) receptors, have been widely used to suppress hyper-aggression. However, the mechanisms underlying the effect of the antipsychotics remain incompletely understood. OBJECTIVES/OBJECTIVE:We reviewed key steps in brain DA synthesis and summarized genetic and pharmacological evidence supporting the role of the mesolimbic DA system in aggression. Next, we discussed recent circuit studies that elucidate the DA action in modulating aggression-related brain regions. These lines of evidence collectively suggest that DA acts on different brain regions to facilitate aggression and self-learning, and signals the valence of the fighting experience.

A social hierarchy is an ordered ranking of individuals that arises through their interactions and governs relative access to resources and social influence. This form of social organization is pervasive across animal species and has a crucial role in shaping survival and reproductive outcomes. Across species, the routes to high status vary widely. As social groups become more complex, the basis of hierarchy shifts from simple residency rules to fighting-based dominance and finally to alliance-based systems. In this Review, we first examine the neuroendocrine and subcortical mechanisms that support status transitions in residency-based hierarchies. We then discuss plasticity within hypothalamic and mesolimbic circuits that underlie fighting-outcome-based social learning, through which fighting-based hierarchies emerge. Finally, we explore alliance-based hierarchies in cognitively complex species, in which individuals attain status through coalition formation, cooperation and reputation. We review evidence that cortical regions encode information about the strengths, emotions, experiences and intentions of other individuals and use this to navigate complex social interactions and attain status. As social hierarchies have shifted from primarily fighting-based to increasingly alliance-based strategies over evolutionary time, neural control of status has, thus, transitioned from subcortical social behaviour circuits to a more elaborated cortical network in humans.

Maternal aggression enables lactating females to protect their vulnerable young^1,2, yet its rapid emergence after birth and swift decline when pups are absent remain poorly understood. Our study reveals the critical role of the pathway from posterior amygdala cells expressing oestrogen receptor alpha (PA^Esr1) to the ventrolateral part of ventromedial hypothalamus cells expressing neuropeptide Y receptor 2 (VMHvl^Npy2r) in the rise and fall of maternal aggression. Projection-specific manipulations and recordings show that PA^Esr1 cells projecting to the VMHvl are naturally active during attack and are required for maternal aggression. During lactation, PA-to-VMHvl^Npy2r synapses potentiate and VMHvl^Npy2r cell excitability increases, enabling heightened aggression. PA^Esr1 neurons express abundant oxytocin receptors, allowing oxytocin to boost PA output; after pup removal, declining oxytocin levels reduce PA drive and dampen maternal aggression, a deficit restored by pup reunion or optogenetic elevation of oxytocin. These findings reveal multiple forms of plasticity in a defined PA^Esr1-VMHvl^Npy2r circuit that collectively implement the adaptive, need-based control of maternal aggression.

In mice and many other species, aggression levels are low in virgin females but increase dramatically during lactation to protect vulnerable offspring. This aggression, aimed at protecting the young, is known as maternal aggression. It emerges abruptly after parturition, peaks during early lactation, and declines after weaning. Given its stereotyped temporal profile, hormones associated with pregnancy and lactation are believed to play critical roles in its rise and fall. In addition, maternal aggression diminishes within hours of pup separation and rapidly recovers upon pup reunion, indicating a secondary, pup-dependent regulation of its expression. Here, we review current knowledge of the female aggression circuit and the hormonal and neural mechanisms that reshape it during pregnancy and lactation. We propose a two-step model in which pregnancy-associated sex hormone surges refine the aggression circuit, while lactation-associated neuropeptide signals gate circuit output in response to the need to protect offspring.

Gonadal hormones act throughout the brain and modulate psychiatric symptoms. Yet how hormones influence cognitive processes is unclear. Exogenous 17β-estradiol, the most potent estrogen, modulates dopamine in the nucleus accumbens core, which instantiates reward prediction errors (RPEs), the difference between received and expected reward. Here we show that following endogenous increases in 17β-estradiol, dopamine RPEs and behavioral sensitivity to previous rewards are enhanced, and nucleus accumbens core dopamine reuptake proteins are reduced. Rats adjusted how quickly they initiated trials in a task with varying reward states, balancing effort against expected rewards. Nucleus accumbens core dopamine reflected RPEs that influenced rats' initiation times. Higher 17β-estradiol predicted greater sensitivity to reward states and larger RPEs. Proteomics revealed reduced dopamine transporter expression following 17β-estradiol increases. Finally, knockdown of midbrain estrogen receptors suppressed sensitivity to reward states. Therefore, endogenous 17β-estradiol predicts dopamine reuptake and RPE signaling, and causally dictates the impact of previous rewards on behavior.

Mothers exhibit an increased appetite to cope with the energetic demands of lactation. A new study has identified a neural circuit that interfaces between food seeking and pup caring.

Becoming a parent involves extraordinary changes that allow caregivers to attend to and nurture infants. Neural circuits must adapt to the demands of caregiving to orchestrate various complex nurturing behaviors. These changes occur between two opposing circuits: a circuit primed for the expression of parenting to execute caregiving, and a circuit that suppresses this behavioral expression when the timing is not appropriate. In this review, we provide an overview of the neural circuits supporting the positive and negative control of parental behaviors and discuss mechanisms by which these opposing circuits are altered to facilitate the onset of parental care.

Seventy % of mammals copulate using repeated pelvic thrusting, while the transfer of sperm requires just a single intromission. Why did thrusting evolve to be the dominant form of sexual intercourse? In this study, we investigate how the rate of sexual pelvic thrusting changes with body size. By analyzing films of copulating mammals, from mice Mus musculus to elephants Elephantidae, we find that bigger animals thrust slower. The rate of pelvic thrusting decreases from 6 Hz for the pocket mouse Pergonathus to 1.3-1.8 Hz for humans to an absence of thrusting for the rhino Rhinocerotidae and elephant Elephantidae families. To understand this dependence on body size, we consider the spring-like behavior of the legs, which is associated with the elasticity of the body's muscles, tendons, and ligaments. For both running and thrusting, a maximum amplitude and great energy savings can be achieved if the system is oscillated at its resonant or natural frequency. Resonant frequencies, as measured through previous studies of running in dogs Canis familiaris and horses Equus ferus caballus, show good agreement with sexual thrusting frequencies. Running and sexual thrusting have nothing in common from a behavioral perspective, but from a physical perspective, they are both constrained by the same musculoskeletal systems, and both take advantage of resonance. Our findings may provide improved treatments for human sexual dysfunction as well as improving breeding strategies for domestic mammals.

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 (ERα). 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. Focusing on rodent studies, in this review we examine classical and contemporary research demonstrating the multifaceted role of estrogen and ERα in regulating social behaviors in a sex-specific and context-dependent manner. We highlight gaps in knowledge, particularly a missing link in the molecular cascade that allows estrogen to exert such a diverse behavioral repertoire through the coordination of gene expression changes. Understanding the molecular and cellular basis of ERα's action in social behaviors provides insights into the broader mechanisms of hormone-driven behavior modulation across the lifespan.