DESCRIPTION (provided by applicant): 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. In Aim 1, we generate high-resolution brainwide maps of endogenous and stimulus-triggered activity patterns in anhedonic states. We use our new readout technologies including ofMRI and COLM as described in the proposal, and our custom recombinase-driver rat lines to allow versatile mechanistic experiments determining if changes in dynamics are linked to altered activity in specific modulatory systems. In Aim 2, we employ another new technology (fiber photometry) to track and quantify local high-speed dynamical patterns corresponding to anhedonia, allowing observation during free behavior of relative balance and joint activity relationships across the brain (initially, we will test for evience of competition between prefrontal cortex and midbrain to exert influence over subcortical limbic pathways during behavior, following up our preliminary findings). In Aim 3, we test causal significance for anhedonia of the changes in dynamics identified in Aims 1 and 2, using new optogenetic tools to modulate coordinated activity relationships across the brain to induce anhedonia from baseline, and restore hedonic behavior in induced anhedonic states. We will also come full circle to Aim 1 measures, quantifying global activity patterns elicited by optical recruitment of the implicated circuit elements, in a final step toward identifying circuit-level phenotypes with causal explanatory power for anhedonic behavior. Together, the approaches proposed here will integrate novel technology to probe fundamental causal underpinnings and mechanisms of a key psychiatric symptom domain in freely-moving mammals.

PUBLIC HEALTH RELEVANCE: An important goal of modern mental health research is finding the neural circuit components and activity patterns that cause psychiatric symptoms. 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 fiber photometry, for collecting dynamical information from deep within the brains of freely-moving mammals; COLM, a novel form of microscopy for global cellular-resolution mapping of activity traces across the entire mammalian brain; and new light-activated ion channels that will allow us to test the causation of anhedonic states. All of these new technologies we have published for the first time this year, highlighting the remarkable alignment in possibility that is taking place. 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.