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: 10002302
• 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/10002302
• 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; 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; cognitive function; coping; depression model; dopaminergic neuron; emotional functioning; 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; 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; 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; cognitive function; coping; depression model; dopaminergic neuron; emotional functioning; 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.

项目摘要 /摘要 从腹侧对盖区（VTA）到内侧前额叶皮层（MPFC）的多巴胺能预测，基础 在许多神经精神疾病中破坏了关键功能。但是，电路级机制通过 前额叶多巴胺调节特定行为的理解仍然很差。科学目标的 该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以及如何相关 前额叶多巴胺改变了这些模式以影响行为。 我的初步研究表明，在前额叶脑切片中激活多巴胺D2受体（D2RS） 增强正相关的活性状态。 D2R被高多巴胺状态优先激活 由VTA神经元的阶段爆发引起。我发现VTA-MPFC的质量刺激，但没有刺激 预测在尾悬架测试（TST）中引起主动应对。最后，我显示了使用活动的体内成像 神经元之间的相关性落在积极的应对过程中，最终过渡到 不动。这些数据表明拟议项目的主要假设，被动应对是由 相关活性和主动应对的分解通过D2R驱动的相关性增加来维持。 在AIM 1中，我将使用光遗传学进一步定义VTA-MPFC中的阶段性和补品模式 传入影响不同的行为。在AIM 2中，我将使用头部安装的Miniscopes确认和扩展 最初的发现，相关性在挣扎期间降低，D1和D2R中的成像活性在表达 子网。在AIM 3中，我将直接改变VTA-MPFC电路元素的活动以建立因果关系 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 我将来的工作的基础使我能够创建一个独立的实验室。 除了进行拟议的研究外，Vikaas Sohal博士将向我指导独立 这项工作将在其实验室中完成。我的科学发展将得到特定方面的帮助 在指导计划中，包括课程，研讨会，期刊俱乐部和会议的演讲。作为 医师，我将通过学习尖端技术来扩大我在治疗抑郁症方面的专业知识 调节大脑的活性。在奖励完成后，我将获得教授职位和 成功地申请了R01赠款，以启动与有关神经电路的独立研究计划 情绪障碍。