PROJECT SUMMARY Aggression is a key aspect of animal social life, playing critical roles in territorial defense, resource acquisition, and protection of offspring. Like other behaviors, aggression is reinforced through experience. This reinforcement often serves beneficial purposes, improving territory defense and protection of offspring – vital behaviors for individual and species survival. However, experience can also promote pathological levels of persistent aggression. In humans, this can harm an individual’s mental health and put others at risk. Thus, there is a need for improved treatment options based on an individual’s prior and on-going history with aggression. Accordingly, my goal is to identify how aggressive experience alters neural circuit computations to generate persistent aggressive behavior. Specifically, this work will probe how experience changes synaptic connectivity and neural activity between two subcortical regions that play critical roles in social behavior: the ventrolateral ventromedial hypothalamus (VMHvl) and medial preoptic area (MPOA). The VMHvl neural activity is necessary and sufficient for aggressive behavior. The MPOA is an influential node regulating many social behaviors and sends the largest source of GABAergic input to the VMHvl. Nevertheless, the role of the MPOA in aggression is enigmatic, and it remains unknown if MPOA inhibitory input to VMHvl can shut down, or gate, aggression or how social experience affects this circuit. To study the MPOA VMHvl circuit, this proposal combines: (1) ex vivo brain slice electrophysiology for optogenetic- assisted circuit mapping and quantification of experience-dependent changes in synaptic strength within the MPOA VMHvl circuit; (2) cell-type and pathway specific calcium recordings in socially interacting mice ; (3) novel algorithms for tracking animal posture dynamics and subsequent methods for unsupervised behavior detection and quantification; and, (4) in vivo optogenetic manipulations to identify the changes in circuit function that link aggressive experience to future persistent aggression. Aim 1 tests the ability of aggressive experience to relax the strength of the synaptic connections between MPOA GABAergic (MPOAvgat) input to distinct, genetically-identified populations of VMHvl neurons. Aim 2 determines if aggressive experience increases in vivo aggression-related VMHvl population activity. Finally, Aim 3 tests the ability of MPOAvgat neurons to gate aggression before and after aggressive experience. Taken together, these experiments will achieve the long-term objective of identifying novel circuit and synaptic treatment targets for aggression- related pathologies based on patients’ behavioral history. Completion of this fellowship will achieve Dr. Guthman’s training goals, providing her with experimental expertise in systems neuroscience to complement her current command of single neuron synaptic physiology. The proposed plan will provide her with the trainin...