Dopaminergic regulation of prefrontal activity patterns during behavior

项目概要/摘要 腹侧被盖区（VTA）到内侧前额叶皮质（mPFC）的多巴胺能投射， 在许多神经精神疾病中，关键功能被破坏。然而，电路级机制， 前额叶多巴胺调节特定行为的机制仍然知之甚少。的科学目标 这个项目是为了确定神经活动的特定模式如何与不同的行为状态相关，以及 前额叶多巴胺会改变这些模式从而影响行为。 我的初步研究表明，激活前额叶脑切片中的多巴胺D2受体（D2Rs） 增强正相关的活动状态。D2R优先被高多巴胺状态激活 诱发VTA神经元的阶段性爆发。我发现VTA-mPFC的相位刺激，而不是强直刺激， 在悬尾试验（TST）中，投射有助于主动应对。最后，我展示了使用体内活动成像 神经元之间的相关性在积极应对的过程中下降，最终过渡到 不动这些数据表明了所提出的项目的主要假设，即被动应对的结果是 相关活动和积极应对的崩溃是由D2R驱动的相关性增加维持的。 在目标1中，我将利用光遗传学进一步确定VTA-mPFC中的阶段性和紧张性活动模式， 传入影响不同的行为。在aim2中，我将使用头戴式微型望远镜来确认和扩大 最初的发现是在挣扎过程中相关性降低，D1和D2R表达的成像活性 子网。在目标3中，我将直接改变VTA-mPFC电路元件的活动，以建立因果关系。 多巴胺和回路活动行为之间的关系。这些结果将建立一个 这是我未来工作的基础，因为这个奖项让我可以开始一个独立的实验室。 除了进行拟议中的研究外，我还将接受Vikaas Sohal博士的独立指导 这项工作将在他的实验室里完成。我的科学发展将得到特定方面的帮助 辅导计划的一部分，包括课程、讲习班、期刊俱乐部和会议上的演讲。作为 作为一名医生，我将继续通过学习尖端技术来扩展我在治疗抑郁症方面的专业知识， 调节大脑的活动到获奖结束时，我将获得教授职位， 我成功地申请了R01资助，以启动一个独立的神经回路研究项目， 情绪障碍

PROJECT SUMMARY / ABSTRACT Dopaminergic projections from ventral tegmental area (VTA) to medial prefrontal cortex (mPFC), underlie critical functions disrupted across many neuropsychiatric conditions. However, the circuit-level mechanisms by which prefrontal dopamine modulates specific behaviors remain poorly understood. The scientific objective of this project is to determine how particular patterns of neural activity relate to distinct behavioral states and how prefrontal dopamine alters these patterns to influence behavior. My preliminary studies have shown that activating dopamine D2 receptors (D2Rs) in prefrontal brain slices enhances a positively correlated activity state. D2Rs are preferentially activated by the high dopamine state induced by phasic bursting of VTA neurons. I find that phasic, but not tonic stimulation of VTA-mPFC projections elicits active coping in the tail suspension test (TST). Finally, I show using in vivo imaging of activity that correlations between neurons fall over the course of active coping bouts, culminating in a transition to immobility. These data suggest the main hypothesis of the proposed project, that passive coping results from a breakdown of correlated activity and active coping is maintained by D2R-driven increases in correlations. In aim 1, I will employ optogenetics to further define how phasic and tonic patterns of activity in VTA-mPFC afferents influence different behaviors. In aim 2, I will use head-mounted miniscopes to confirm and expand the initial finding that correlations degrade during struggling, imaging activity in D1 and D2R expressing subnetworks. In aim 3, I will directly alter activity in elements of VTA-mPFC circuitry to establish causal relationships between dopamine and circuit activity-behavior relationships. These results will establish a foundation for my future work as this award allows me to start an independent laboratory. In addition to conducting the proposed studies, I will be mentored towards independence by Dr. Vikaas Sohal in whose laboratory this work will be accomplished. My scientific development will be aided by specific aspects of the mentoring plan, including coursework, workshops, journal clubs and presentations at conferences. As a physician, I will continue to expand my expertise in treating depression by learning cutting-edge techniques to modulate activity in the brain. By the completion of the award, I will have obtained a professorship and successfully applied for an R01 grant to launch an independent research program in neural circuits related to mood disorders.