Dissociable neural mechanisms of reactive versus appetitive aggression

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Project Summary Maladaptive aggression characterizes - or is comorbid with - many neuropsychiatric illnesses, and can have devastating effects on individuals, their caretakers, and healthcare professionals. Human aggression is typically demarcated as exhibiting either reactive (defensive) or appetitive (rewarding) components, and a growing literature indicates they are heavily influenced by dysregulation in amygdalar or reward circuitry, respectively. Despite a significant clinical awareness of the fundamental differences between these aggression presentations, direct preclinical characterization of their relative circuitry and associated neuronal mechanisms are currently absent. Therefore, the aim of my proposal is to obtain the obtain the necessary computational, behavioral and anatomical training to identify, interrogate, and manipulate neural populations that modulate these disparate aggressive behaviors. This project will focus on identifying lateral septum (LS) circuit and cell-type specific mechanisms that control of reactive versus appetitive aggression, and then further interrogate the afferent projections driving these populations. The choice of this brain region is based on converging preliminary data, including my own, implicating that the LS may confer opposing roles in regulating appetitive versus reactive aggression. The circuit and cell-type specific activation of the LS will be identified using a combination of Fos (a marker of neuronal activity) immunohistochemistry, multiplex in situ hybridization, and retrograde viral tracing. Because of the limited temporal resolution of Fos during these behaviors, awake-behaving fiber photometry recording will be used to observe how LS neurons encode these types of aggression in real-time. Next, the causal significance of the LS and its afferent projections will be examined using region, circuit, and cell-type specific optogenetic manipulations. Understanding the neural mechanisms driving these types of aggression will allow for the development of more specific and effective treatments for maladaptive aggression presenting comorbid with neuropsychiatric disorders.