Prefrontal Circuit Control of Isolation-Induced Aggression

PROJECT SUMMARY/ ABSTRACT Extended deprivation of social contact can produce deleterious effects on the brain and behavior. Social isolation (SI), or its perception (loneliness), is as predictive a risk factor for poor health outcomes as smoking or obesity. Many factors have contributed to a modern epidemic of loneliness: a growing aging population, dramatic changes to our social structure (technology, social media), the opioid crisis, and, most recently, the COVID-19 pandemic. One of the most damaging impacts of SI is the promotion of interpersonal aggression and violence against others – indeed, SI-associated domestic violence has risen by 20%, rates of suicide have surged, and school shootings continue to rip at the fabric of society. Despite this, we have a poor understanding of the genetically-defined, circuit mechanisms that give rise to isolation-induced aggression, representing a critical barrier for the development of targeted interventions and cognitive therapies to treat pathological forms of aggression. One key brain region known to exert top-down, cognitive control over behavior, including aggression, is the medial prefrontal cortex (mPFC). However, the role of the mPFC in modulating the effects of SI-induced aggression is unknown. In the project proposed here, we will interrogate the function of distinct, genetically-defined cells in the mPFC to modulate SI-induced aggression. In support of this, we recently identified the neuropeptide Tachykinin 2 (Tac2)/Neurokinin B (NkB) as a key, subcortical mediator of SI. Here, we will test whether Tac2 signaling in the mPFC exerts cortical control of SI-aggression. In preliminary studies, we have discovered that Tac2+ mPFC neurons comprise a unique, unexplored class of GABAergic interneurons (INs). These findings lead to the specific hypothesis that Tac2+ INs exert feed-forward inhibition of excitatory pyramidal neurons (PNs) to mediate SI-aggression. To test this, we will combine behavior, machine learning, molecular-genetic loss- and gain-of function manipulations, and in vivo Ca2+ imaging to achieve a circuit-level, mechanistic understanding of how distinct populations of genetically-defined neurons in the mPFC exert coordinated, cortical control of SI- aggression. We will determine whether mPFC Tac2+ neurons are required for SI-aggression (Aim 1), whether mPFC PNs are sufficient to inhibit SI-aggression (Aim 2), and whether Tac2+ INs directly regulate PN activity during SI-aggression (Aim 3). Collectively, we aim to uncover a conserved, genetically-defined mPFC microcircuit for the top-down, cortical control of isolation-induced aggression. These findings will transform the field by expanding our understanding of how pathological forms of aggression are encoded and controlled by prefrontal circuits in the brain. Importantly, this research will have profound implications for the treatment of social isolation-related mental health disorders, particularly those that result in violence.