Top-down regulation of compulsive reward-seeking behavior by medial prefrontal cortex

 描述（由申请人提供）：虽然寻求奖励的驱动力是许多物种共有的基本特征，但如果不加以控制，它可能导致成瘾和药物滥用。一种潜在的治疗成瘾的方法可能是重新调整驱动和抑制奖励寻求的神经回路之间的平衡。为了实现这种方法，我们必须描述强迫性奖赏寻求所发生的特定神经状态变化，并确定可以逆转这种行为的神经通路。本研究旨在利用双光子成像技术揭示腹侧被盖区多巴胺神经元在一种强迫性奖赏寻求行为--光遗传学自刺激过程中的神经活动模式。这将揭示神经动力学的变化，这些变化伴随着反复的、强迫性的奖赏寻求，而奖赏寻求是成瘾的基础。此外，该提案将测试内侧前额叶皮质（mPFC）刺激是否能够通过改变在NAc中观察到的神经活动模式来发挥调节作用，以减少强迫性奖励寻求。最后，该提案的目的是确定哪些特定的mPFC投射神经元使用细胞类型特异性狂犬病GCaMP 6和纤维光度成像驱动奖励寻求行为的抑制。这个项目的研究结果将提供一个新的见解，了解NAc电路动态在成瘾过程中如何改变，以及这些变化如何被mPFC自上而下的执行控制所抵消。

 DESCRIPTION (provided by applicant): While the drive to seek reward is a fundamental trait shared across many species, when left unchecked it can lead to addiction and substance abuse. A potential therapeutic approach to treating addiction could be to reset the balance between the neural circuits that drive and suppress reward-seeking. To achieve such an approach, we must characterize the specific neural state changes that occur with compulsive reward-seeking, and identify the neural pathways that can reverse this behavior. This proposal aims to use 2photon imaging to reveal the neural activity patterns in the nucleus accumbens (NAc) during a type of compulsive reward-seeking behavior, optogenetic self-stimulation of the ventral tegmental area dopamine neurons. This will reveal the changes in neural dynamics that emerge with repeated, compulsive reward-seeking which underlies addiction. In addition, this proposal will test whether medial prefrontal cortex (mPFC) stimulation is able to exert regulatory action to reduce compulsive reward-seeking by altering the neural activity patterns that are observed in NAc. Finally, this proposal aims to identify which specific mPFC projection neurons drive suppression of reward-seeking behaviors using cell type-specific rabies GCaMP6 and fiber photometry imaging. The findings from this proposed project will provide a novel insight into how NAc circuit dynamics become altered during addiction, and how these changes may be counteracted by top-down executive control from the mPFC.