Brain hedonic circuitry mediating 'liking' and 'wanting' for reward

项目总结/摘要：正常的享乐功能，或对积极情感的“喜欢”反应 1 -3快乐脑回路功能障碍可能导致情绪障碍， 成瘾和饮食失调。1.4奖励“喜欢”的大脑机制仍然相对不太清楚， 激励机制（“想要”）和奖励学习。“喜欢”的反应可以被放大， 享乐热点网络，这些热点是脑桥核、腹侧苍白球、眶额 皮层和皮层，当神经化学或光遗传学刺激时， 增加可口奖励的享乐影响。1，5 -10本提案的主要目标是促进 通过研究享乐主义之间的回路水平功能相互作用来理解“喜欢”回路 热点，放大“喜欢”，检查神经元编码的“喜欢”的影响，在享乐热点， 巩固了我在前扣带皮层发现的一个新的享乐热点。到目前为止，我已经证明， 在吻内侧眶额皮质、后腹苍白球和尾侧苍白球中的光遗传学激活热点 相反，光遗传学抑制对蔗糖的口面“喜爱”反应， 腹侧苍白球热点对正常情况下“喜欢”的甜食产生病理性的强烈“厌恶”反应。 在GAD 1-Cre大鼠中使用细胞特异性光遗传学技术，我进一步表明， 腹侧苍白球热点专门负责双向控制“喜欢”（目的1）。F99阶段 该奖项将进一步测试多个热点一致招募来控制“喜欢”的假设 当一个热点被刺激时（目标2c-b），这将证实我在尾部发现了一个新的享乐热点。 前扣带皮层（Aim 2a）。我将使用光遗传学ChR 2刺激来激发热点并分析Fos 在其他热点的表达模式，以确认招聘。此外，使用体内钙成像，我将 确认当OFC热点为光遗传学时腹侧苍白球GABA热点神经元的募集 刺激以产生“喜欢”增强。我还将测试一致招募的必要性， 光遗传学刺激一个享乐热点（例如OFC），同时破坏另一个享乐热点（例如VP）。 拟议的培训将有助于我过渡到一个有竞争力的博士后奖学金，让我， 学习免疫组织化学、双部位脑操作和体内钙成像。对于KOO阶段 （目标3），我将确定一个博士后实验室，使我能够调查如何稳态电路调节奖励 系统的功能是影响“喜欢”和“想要”的反应。我对享乐奖励 系统与下丘脑中的调节饥饿/饱足回路相互作用。F99/K 00奖将是无价的 通过促进分子，遗传学和生物学方面的博士后培训， 电生理技术，将补充我目前在享乐电路操纵的专业知识。 总的来说，这项工作可能有助于阐明情感性精神障碍中享乐功能障碍的神经机制。

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.