Dopaminergic regulation of prefrontal activity patterns during behavior

项目摘要/摘要 腹侧被盖区(VTA)至内侧前额叶皮质(MPFC)的多巴胺能投射 许多神经精神疾病的关键功能都中断了。然而，电路级机制通过 前额叶的哪种多巴胺调节特定的行为仍然知之甚少。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，以及如何 前额叶多巴胺改变这些模式以影响行为。 我的初步研究表明，激活前额叶脑片中的多巴胺D2受体(D2Rs) 增强一种正相关的活动状态。D2Rs优先被高多巴胺状态激活 由VTA神经元时相性爆发所致。我发现VTA-mPFC的时相刺激，但不是紧张性刺激 在尾部悬挂试验(TST)中，投射引起积极应对。最后，我展示了使用活体成像的活动 神经元之间的相关性在积极应对的过程中下降，最终转变为 一动不动。这些数据表明了拟议项目的主要假设，即被动应对源于 相关活动和积极应对的分解是由D2R驱动的相关性增加维持的。 在目标1中，我将使用光遗传学来进一步定义VTA-mPFC的时相和紧张性活动模式 传入会影响不同的行为。在目标2中，我将使用头戴式微型显微镜来确认和扩展 初步发现在搏斗过程中相关性降低，影像活动在D1和D2R表达 子网络。在目标3中，我将直接改变VTA-mPFC电路元件的活动以确定因果关系 多巴胺与电路活动-行为关系之间的关系。这些结果将建立一个 为我未来的工作奠定基础，因为这个奖项允许我开始一个独立的实验室。 除了进行拟议的研究外，维卡斯·索哈尔博士还将指导我走向独立 这项工作将在谁的实验室完成。我的科学发展将得到特定方面的帮助 指导计划，包括课程作业、研讨会、期刊俱乐部和在会议上的陈述。作为一名 医生，我将继续通过学习尖端技术来扩大我治疗抑郁症的专业知识 调节大脑的活动。在完成颁奖时，我将获得教授职位，并 成功申请R01拨款，启动与以下相关的神经电路独立研究计划 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.