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.
