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

 描述(由申请者提供)：虽然寻求回报的驱动力是许多物种共有的基本特征，但如果不加以控制，可能会导致上瘾和药物滥用。治疗成瘾的一种潜在的治疗方法可能是重置驱动和抑制奖赏寻求的神经回路之间的平衡。为了实现这种方法，我们必须表征强迫性寻求奖励时发生的特定神经状态变化，并确定可以逆转这一行为的神经路径。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--光发生自我刺激过程中伏核(NAC)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、强迫性的奖赏追求，这是成瘾的基础。此外，这项提议将测试刺激内侧前额叶皮质(MPFC)是否能够通过改变在NAC观察到的神经活动模式来发挥调节作用，以减少强迫性奖赏寻求。最后，这项建议旨在利用细胞类型特定的狂犬病GCaMP6和纤维光度成像来确定哪些特定的mPFC投射神经元驱动对奖赏寻求行为的抑制。这一拟议项目的发现将为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提供了一个新的见解。

 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.