PROJECT SUMMARY Neural activity in the neocortex is plastic over a range of temporal scales. Learning associations between sensory stimuli and behaviorally relevant outcomes drives cortical plasticity and is fundamental to an organism’s survival. Chronic stress can also impact neural circuits although its contributions to sensory cortex connectivity and sensory encoding is unclear. Changes in information processing in the neocortex can take place at different spatial scales: in local microcircuits made up of heterogeneous excitatory and inhibitory cell types and in larger interconnected cortical networks. Rodent studies from the last decade have revealed an elaborate network of secondary visual areas that may be involved in visually-guided behaviors such as associating initially neutral visual stimuli with aversive events. However, the dynamic network connectivity of these secondary areas and their distinct contributions to learned, visually guided fear behavior is unknown. Fear-learning enhances the cortical representation of stimuli that predict a foot shock, but it is currently unknown if different inhibitory elements support these changes in visual stimulus representations. Using innovative imaging approaches this proposal will address 3 Aims: (1) Determine the changes in network dynamics and functional connectivity that accompany fear learning. The proposed experiments will investigate primary and secondary visual cortical contributions to learned fear behavior using simultaneous dual 2-photon/widefield imaging and cortical inactivation approaches. (2) Determine the microcircuits that contribute to fear-learning related changes in cortical responses. Using cell-type specific 2-photon imaging and optogenetics Dr. Moberly will test the hypothesis that VIP-mediated disinhibition enhances cortical output neuron responses. (3) Investigate the consequences of stress for functional sensory cortical network architecture and its relationship to ongoing behavioral state. Dr. Moberly will conduct this research in the labs of his mentors Drs. Jessica Cardin and Michael Higley at the Yale University School of Medicine with input from advisory committee members, Drs. Marina Picciotto and Michael Crair. In the K99 period, Dr. Moberly will learn new technical skills in cellular 2-photon and simultaneous dual 2-photon/widefield imaging in combination with optogenetics and quantitative behavioral approaches. The proposed experiments and multifaceted training plan will impart Dr. Moberly with a unique combination of skills that will position him to transition into a successful independent career as a systems neuroscientist.

PROJECT NARRATIVE Cortical circuit flexibility is influenced by learning and impacted by repeated stressors. The proposed research will focus on how fear learning and chronic stress modulate cortical activity in local microcircuits and large-scale networks. This work will provide new insights into behaviorally relevant plasticity in visual cortical circuits with implications for basic science as well as stress-related pathophysiology.