Project Summary/Abstract: Positive affective reactions (i.e., ‘liking’) to pleasant life events are crucial to healthy psychological function and well-being. Conversely, pathological hedonic dysfunction in ‘liking’ circuitry can cause loss of positive affect (anhedonia), and excessive negative affect (dysphoria). These affective dysfunctions have devastating consequences in mood disorders, such as major depression, bipolar disorder, schizophrenia, etc. It is therefore crucial to understand how normal brain affective mechanisms generate positive ‘liking’ reactions, and how dysfunction in brain ‘liking’ circuitry causes intense negative dysphoric affective reactions, in order to develop better treatment for mood disorders. This proposal aims to make progress towards those goals. Our previous studies identified a network of specialized brain mechanisms, or pleasure-amplifying hedonic hotspots, that generate intense ‘liking’ reactions. These pleasure-intensifying hedonic hotspots are small specialized subregions contained within limbic orbitofrontal cortex, insula, nucleus accumbens and ventral pallidum, where optogenetic or neurochemical neural stimulations are able to enhance ‘liking’ reactions. Our previous studies also identified dysfunction in hedonic hotspots that produced excessive negative affect. Yet the specific hedonic coding mechanisms within each brain hedonic hotspot that cause ‘liking’ still remain unclear. Also unknown is how the hedonic hotspots functionally work together, to form a larger and integrated hedonic brain circuit. Finally, it is unknown how particular neural dysfunctions in hedonic hotspots cause intense negative ‘fear’ or ‘disgust’ reactions, or whether such excessive negative affect can be successfully reversed. The studies proposed here will use sophisticated optogenetic and affective neuroscience techniques to answer these questions. The results will provide insights into brain hedonic circuitry, which in turn can provide a better scientific basis to guide development of future therapies for anhedonia, anxiety and dysphoria disorders.