Aggression is an innate social behavior prevalent among mammalian species including human. In the quest to comprehend the neural substrates underlying aggression, we use a genetically tractable model organism, namely mice, which show a high level of territorial aggression in the laboratory setting. Our recent studies found tha inactivation of ventromedial hypothalamus ventrolateral part (VMHvl) suppresses natural territory aggression while optogenetic activation of neurons in the VMHvl can induce appetitive approach as well as consummatory attack towards conspecific intruders. Under certain circumstances, the approach and attack can be induced independently. Furthermore, chronic in vivo recording reveals that many VMHvl cells begin to increase activity prior to any physical contact with an intruder, escalate during approach, and reach peaks during attack; a small fraction of cells are activated only during attack. Taken together, these results indicate that VMHvl may drive both appetitive approach and consummatory attack, and separate pathways may mediate these two aspects of aggression. This project will test this hypothesis and identify other relays extended from the VMHvl in the aggression circuit. As VMHvl contains cells with heterogeneous functions, we will first identify the synaptic targets of aggression related cells by examining the colocalization of fighting induced immediate early gene expression and retrogradely labeled signals from a candidate downstream region in the VMHvl. Once an anatomical area is identified as a synaptic target of VMHvl aggression cells, we will manipulate activity in the region using various pharmacological or pharmacogenetic means and examine changes in social approach and attack behaviors. Furthermore, we will manipulate the target region in tandem with VMHvl activation to examine whether the candidate area is an essential node between VMHvl output and motor execution. Finally, to understand how the VMHvl output is organized to drive downstream cells, we will relate the cell function to its connectivity by recording VMHvl cells with antidromically identified projection patterns in freely moving animals. At the output end, we will record cells in the downstream regions and examine how the VMHvl information is filtered and transformed along the aggression pathway. This project will not only address a basic question in neuroscience regarding how instinct behavior is generated but also provide a neural circuit diagram for developing potential treatments for pathological aggression.

Public Health Relevance

Violence imposes a devastating risk to our society, and our relative inability to predict and control aggression stems from our ignorance of the neural mechanism(s) underlying its generation and modulation. Our previous study identified the ventromedial hypothalamus, ventrolateral part (VMHvl), as an indispensible relay for male mouse aggression. This project will use the VMHvl as our entry point to deconstruct the 'appetitive' and 'consummatory' aggression pathways, providing a basic framework for diagnosis and treatment of pathological aggression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular Neurogenetics Study Section (MNG)
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Simmons, Janine M
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New York University
Schools of Medicine
New York
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