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

项目摘要/摘要：正常的享乐功能，或对积极情感的“喜欢”反应 事件对心理健康是必不可少的。1-3享乐性大脑回路功能障碍可能会导致情绪障碍， 上瘾和饮食失调。1，4奖励“喜欢”的大脑机制仍然相对较少被理解 激励激励(想要)和奖励学习的机制。“喜欢”的反应可以用一种 享乐热点网络，即伏隔核、腹侧苍白球、眶前叶的小亚区 当神经化学或光基因刺激时，大脑皮层和脑岛具有独特的因果关系 增加令人愉快的奖励的享乐主义影响。1，5-10这项提议的主要目标是推进 通过研究享乐之间的电路级功能相互作用来理解“喜欢”的电路 放大“喜欢”的热点，检查享乐热点中“喜欢”影响的神经元编码，以及 巩固了我在前扣带回皮质发现的一个新的享乐主义热点。到目前为止我已经证明了 旋转内侧眶前叶皮质、苍白球后腹侧和尾侧的光遗传激活热点 脑岛使面部对蔗糖的“喜欢”反应加倍。9，10相反，光遗传抑制了 腹侧苍白球热点会对正常的“喜欢”的甜味产生病理性的强烈“厌恶”反应。 利用GAD1-CRE大鼠的细胞特异性光遗传学技术，我进一步表明，在GAD1-CRE大鼠体内，GABA能神经元 腹侧苍白球热点专门负责双向控制“喜欢”(目标1)。F99阶段 该奖项的颁发将进一步检验这样一种假设，即一致招募多个热点来控制“点赞”。 当一个热点被刺激时(目标2c-b)，并将证实我在尾部发现了一个新的享乐热点 前扣带回皮质(目标2a)。我将使用光遗传ChR2刺激来激发热点并分析Fos 在其他热点地区的表达模式，以确认招募。此外，使用活体钙成像，我将 确认OFC热点为光遗传时腹侧苍白球GABA热点神经元的募集 被刺激以产生“喜欢”的增强。我还将通过以下方式测试一致招募的必要性 光遗传刺激一个享乐热点(如OFC)，同时干扰另一个(如VP)。 拟议的培训将帮助我过渡到竞争激烈的博士后奖学金，使我能够 学习免疫组织化学、双部位脑操作和体内钙成像。古永锵阶段 (Aim3)，我将找到一个博士后实验室，使我能够研究体内平衡电路如何调节奖赏 系统功能影响“喜欢”和“想要”的反应。我特别感兴趣的是享乐主义的奖励 系统与下丘脑的饥饿感/饱腹感调节回路相互作用。F99/K00奖将是无价的 通过促进博士后在分子、基因和 电生理技术将补充我目前在享乐电路操作方面的专业知识。 总体而言，这项工作可能有助于阐明情感性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.