Selecting future actions based on previous experiences is key to an animal's survival. This process, known as action selection, depends on the proper function of cortical and subcortical basal ganglia circuits. Despite the importance of these regions for using previous experiences to inform upcoming motor choices, we do not understand the precise mechanisms by which these regions work together and the activity patterns they use to select actions. The significance of these regions in action selection is clear in disorders that arise from cortical and basal ganglia dysfunction. One hypothesis is that the cortex develops motor plans that the basal ganglia then executes and evalulates based on outcome. Based on anatomy, we know that cortex and basal ganglia form a recurrent loop in the brain, however we do not understand how the two work together to promote and select actions. This gap in knowledge is due in part to our lack of technology to assess and perturb cortex and basal ganglia simultaneously. In this proposal, I will overcome these limitations by examining the recurrent interactions between the cortex and basal ganglia during ongoing action selectin. I will focus on the mouse anterior lateral motor cortex (ALM) and the striatum, the primary input nucleus of the basal ganglia. My overarching hypothesis that striatal activity is modified based on action outcome and its recurrent feedback to ALM is necessary to update subsequent motor planning required for action selection. To test my hypothesis, I plan to implement 2-photon calcium imaging in ALM, large-scale electrophysiology in striatum, site-specific striatal perturbations, and a two-choice motor task which uses past information to produce future actions. In this proposal, I will determine 1) how striatal activity influences motor planning in ALM during action selection, and 2) if striatal activity is necessary for proper action updating in ALM during action selection. Together, these aims will tell us how cortical and striatal circuits dynamically interact to produce ongoing behavior. My research goals are to investigate the fundamental mechanisms by which striatum and cortex contribute to action selection. My academic goals are to build a strong foundation in computational neuroscience and continue to improve the career development skills I will need for my transition to independence at the end of this fellowship. The lab of my sponsor, Dr. Bernardo Sabatini, and the Harvard Medical School community will provide an excellent training environment for this fellowship. Dr. Sabatini is a leading expert in basal ganglia physiology, 2-photon imaging, and the analysis of neural data. The Sabatini lab and the Department of Neurobiology at Harvard Medical School will provide excellent career development resources for training in neurobiology with a strong focus on collaboration and scientific innovation.
The research proposed in this application will employ cutting edge 2-photon microscopy, large-scale electrophysiology, and head-fixed behavior to test hypotheses about cortical and subcortical structures and their involvement in action selection. The results will provide insight into how specific patterns of activity in the brain drive the selection and modification of ongoing behavior and motor output.