Dopaminergic regulation of prefrontal activity patterns during behavior

行为过程中前额叶活动模式的多巴胺能调节

• 批准号: 9753372
• 负责人: Scott Allen Wilke
• 金额: $ 19.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753372
• 关键词: Address; Affect; Award; Behavior; Behavioral; Biological Assay; Brain; Cognitive; Complex; Coping Behavior; Data; Data Set; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Educational workshop; Elements; Emotional; Exhibits; Fire - disasters; Foundations; Future; Goals; Grant; Head; Image; Ion Channel; Journals; Laboratories; Learning; Light; Link; Medial; Mental Depression; Mental disorders; Mentors; Microscope; Mood Disorders; Moods; Mus; Neurons; Pattern; Phase; Physicians; Pilot Projects; Positioning Attribute; Prefrontal Cortex; Process; Receptor Activation; Regulation; Research; Role; Slice; Stress; Tail Suspension; Techniques; Testing; Ventral Tegmental Area; Work; addiction; behavior influence; behavioral response; career development; coping; depression model; dopaminergic neuron; experimental study; falls; hedonic; in vivo; in vivo imaging; learning strategy; neural circuit; neural patterning; neuropsychiatry; optogenetics; programs; relating to nervous system; response; symposium; tool

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.

项目概要/摘要 从腹侧被盖区 (VTA) 到内侧前额皮质 (mPFC) 的多巴胺能投射 许多神经精神疾病的关键功能都受到了干扰。然而，电路级机制 前额叶多巴胺调节特定行为的机制仍知之甚少。科学目标 该项目旨在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来影响行为。 我的初步研究表明，激活前额叶脑切片中的多巴胺 D2 受体 (D2R) 增强正相关的活动状态。 D2R 优先被高多巴胺状态激活 由 VTA 神经元的阶段性爆发引起。我发现 VTA-mPFC 是阶段性的，但不是强直性的刺激 预测会在悬尾测试（TST）中引发积极应对。最后，我展示了使用活体成像 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。这些数据表明了拟议项目的主要假设，即被动应对是由于 相关活动和积极应对的崩溃是由 D2R 驱动的相关性增加来维持的。 在目标 1 中，我将利用光遗传学来进一步定义 VTA-mPFC 活动的相位和强直模式 传入影响不同的行为。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 D1 和 D2R 表达的成像活动中，相关性会降低 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了基础，因为这个奖项使我能够建立一个独立的实验室。 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具体方面的帮助 指导计划，包括课程作业、研讨会、期刊俱乐部和会议演讲。作为一个 作为医生，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 调节大脑活动。完成该奖项后，我将获得教授职位 成功申请R01资助，启动神经回路相关的独立研究项目 情绪障碍。