This proposal is designed to provide circuit-dynamics understanding of anhedonia, a psychiatric symptom domain of enormous clinical significance that is well-suited for study in laboratory animals. This work, alongside our recently-developed methods for obtaining brainwide cellular-resolution activity readout and control, has created a powerful and fortuitous alignment enabling us to bridge local and global neuronal dynamics, and to identify brain-spanning circuitry mediating behavioral drives, conflicts, and resolutions. In Aim 1, we identify single-cell-resolved orbitofrontal (OFC) dynamics underlying distinct consummatory behaviors. We have developed a temporally-precise alternative-choice mouse-behavioral paradigm, crucially designed for compatibility with our wide-field cellular-resolution imaging/recording methods, in which mice select among multiple motivational drives, and adjust action planning in light of internal or external context. We apply this paradigm along with our cellular-resolution readouts and analyses, beginning with addressing both hunger and thirst in OFC. We identify dynamics of motivational drive resolution both in the presence or absence of controlled internal states, and in the presence or absence of external (social) context, using our new methods; we hypothesize from prior work (Jennings et al., Nature 2019) that resolution of these conflicts will depend upon not only the motivational (internal) state of the animal but also the external context. In Aim 2, we map causal global dynamics of motivational drive conflict and resolution, quantifying the high-speed cellular-resolution brainwide circuit dynamics underlying these motivational drive interactions (drives naturally-occurring; or, to leverage our fast electrophysiological readout, instead induced in temporally- precise fashion by optogenetically driving AGRP neurons in the case of hunger, and/or SFO inputs to the MnPO in the case of thirst, using our established models and methods; Allen et al., Science 2019; Jennings et al., Nature 2019; Marshel et al., Science 2019). Identification of novel region-specific dynamics in conditions of varying motivational drive and social context will feed back to inform Aim 1 imaging workflow, already with a firm foundation from our prior work imaging OFC states corresponding to social and thirst drive interaction. In Aim 3, we define cells underlying inter-drive competition and corresponding brainwide dynamics. Multiple single cells identified by natural activity will be optogenetically targeted with our unique wide-field and high-resolution spatial light-guidance technology. We register cellular ensembles observed to be naturally and causally involved, to detailed 3D intact-tissue (STARmap) transcriptomic information from the same cells in the same organism. Alignment with wiring-based anatomy and deep molecular datastreams allow cell-type- resolved and single cell-level insight into, and targeting of, survival drive competition and resolution processes, with both basic significance and relevance to brain disease. Together, the approaches proposed here will integrate novel technology to probe causal underpinnings of key symptom domains in freely-moving mammals.

An important goal of modern mental health research is finding the neural circuit components and activity patterns that cause psychiatric symptom; a remarkable convergence of new technologies is occurring that may allow a fundamental leap forward in such circuit-level understanding of anhedonia (the loss of reward from experience), a defining symptom in, among other conditions, the disease of major depressive disorder. These technologies include mechanisms for collecting cellular-resolution dynamical information from deep within the brains of freely-moving mammals—and technologies that will allow us to test the causation of anhedonic states. Insight into the circuit dynamics of anhedonia may not only guide development of new, potent, and specific therapies, but will also contribute to our basic understanding of how neural circuit activity patterns give rise to behavior, with potential relevance to many neuropsychiatric diseases such as depression and schizophrenia.