Brain hedonic circuitry mediating 'liking' and 'wanting' for reward - PROJECT SUMMARY/ABSTRACT: Normal hedonic function, or `liking' reactions to positive affective events, is essential for mental health.1–3 Dysfunction in hedonic brain circuitry may contribute to mood disorders, addiction, and eating disorders. 1,4 Brain mechanisms of reward `liking' remain relatively less understood than mechanisms of incentive motivation (`wanting) and reward learning. `Liking' reactions can be amplified by a network of hedonic hotspots, which are small subregions of nucleus accumbens, ventral pallidum, orbitofrontal cortex, and insula that are uniquely able, when neurochemically or optogenetically stimulated, to causally increase the hedonic impact of palatable rewards.1,5–10 The primary goal of this proposal is to advance understanding of `liking' circuitry by investigating circuit-level functional interactions between hedonic hotspots that amplify `liking', examining neuronal coding of `liking' impact within hedonic hotspots, and consolidating my discovery of a novel hedonic hotspot in anterior cingulate cortex. To date I've shown that optogenetically activating hotspots in rostromedial orbitofrontal cortex, posterior ventral pallidum, and caudal insula doubles affective orofacial `liking' reactions to sucrose.9,10 Conversely, optogenetically inhibiting the ventral pallidum hotspot generates pathologically intense `disgust' reactions to normally `liked' sweetness.10 Using cell-specific optogenetic techniques in GAD1-Cre rats, I've further shown that GABAergic neurons in the ventral pallidum hotspot are specifically responsible for bidirectional control of `liking' (Aim 1). The F99 phase of this award will further test the hypothesis that multiple hotspots are unanimously recruited to control `liking' when one hotspot is stimulated (Aim 2c-b), and will confirm my discovery of a novel hedonic hotspot in caudal anterior cingulate cortex (Aim 2a). I will use optogenetic ChR2 stimulation to excite a hotspot and analyze Fos expression patterns in the other hotspots to confirm recruitment. Further, using in vivo calcium imaging, I will confirm recruitment of ventral pallidum GABA hotspot neurons when the OFC hotspot is optogenetically stimulated to generate `liking' enhancements. I will also test the necessity of unanimous recruitment by optogenetically stimulating one hedonic hotspot (e.g. OFC) while simultaneously disrupting the other (e.g. VP). The proposed training will facilitate my transition to a competitive postdoctoral fellowship by allowing me to learn immunohistochemistry, dual site brain manipulations, and in-vivo calcium imaging. For the KOO Phase (Aim3), I will identify a postdoctoral lab enabling me to investigate how homeostatic circuitry modulates reward system functions to influence `liking' reactions and `wanting'. I have particular interest in how hedonic reward systems interact with regulatory hunger/satiety circuits in hypothalamus. A F99/K00 award will be invaluable towards my transition to independence by facilitating postdoctoral training in molecular, genetic, and electrophysiological techniques that will complement my current expertise in hedonic circuitry manipulations. Overall, this work may help elucidate neural mechanisms underlying hedonic dysfunction in affective disorders.
