Contributions of activity-defined cortical ensembles to brainwide reward processing

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Project summary This proposal seeks to establish the contribution of specific patterns of neural activity in the medial prefrontal cortex (mPFC) to brainwide reward processing during reward-seeking tasks. The mPFC is known to be important for processing rewards in the environment and selecting the appropriate reward-seeking actions. A missing link in our understanding of why mPFC is important for these behaviors is determining how patterns of neuronal activity in mPFC drive neurons across the brain to influence an individual’s behavior. In this proposal, by taking advantage of the most recent technologies to monitor and manipulate neural activity, I plan to test the functional contribution of specific ensembles of neurons in mPFC to the brainwide activity. I will specifically test the neural dynamics underlying a Pavlovian reward-seeking task that models the ability of certain environmental cues to drive reward (and drug) seeking, a phenomenon with which mPFC is closely linked. In aim 1, I will use two-photon calcium imaging to measure the activity of individual mPFC neurons while mice are licking for sucrose reward in response to reward-predicting cues. I will then use an optogenetic approach with patterned laser illumination to selectively activate specific mPFC neurons, producing targeted alteration of population activity patterns. By determining which activity impacts the mouse’s behavior during the task, this aim will address hypotheses about which aspects of population coding in mPFC determine its impact on behavior. In aim 2, I will use high density recording devices (Neuropixels probes) to measure the activity of thousands of neurons in nine major output regions of mPFC while manipulating subsets of mPFC cells during the reward-seeking task. In this aim I will determine how manipulations of mPFC activity change reward-related representations across the brain, honing in on the neural circuit mechanisms by which mPFC shapes reward-seeking behavior. Together these aims will establish how different ensembles of cells in mPFC coordinate brain-wide neural activity to guide reward seeking, and more generally how ensembles of neurons function in distributed circuits to generate behavior. This line of research will have particular relevance to disorders (like addiction) that involve reward-processing systems in the nervous system. The mPFC is already a region of interest for clinical intervention because of its role in relapse. Understanding which features of mPFC population activity participate in which aspects of reward seeking, as well as how mPFC interacts with other brain regions, will greatly improve the precision with which we can target mPFC therapeutically.