Lateral habenula circuit in reward/conflict mediation

项目摘要 奖励通常出现在危险的环境中，要求个人权衡奖励的好处和 与之相关的风险。在几种精神障碍中，患者无法选择 在有风险的奖励机会中做出适当的反应。一些有成瘾障碍的患者被驱使 以高昂的成本和生活质量为代价寻求回报，而一些患有严重疾病的患者 抑郁症患者往往对惩罚过于敏感，错过了奖励机会。近期 研究表明，外侧缰核(LHb)、腹侧苍白球(Vp)和伏核 (NAC)是调节积极和消极动机的关键结构，也是涉及这些结构的回路 可以支配冲突行为。在这个方案中，我们将研究特定细胞类型的NAC-VP-LHb的作用 小鼠冲突行为中的回路。我们将使用一种新的冲突任务，在这个任务中，口渴、行为自由的小鼠 主动选择是寻求水的奖励，还是通过移动来避免脚部电击的惩罚 送到一个安全平台。由于水口和安全平台相隔很远，老鼠被摆成一个 是为了奖励还是为了逃避惩罚的冲突。我们将使用光遗传、化学遗传和 用光度成像方法表征NAC-VP-LHb电路中细胞类型的特定投射 调解冲突行为。目的1(K99)，我们将描述LHb在冲突行为中的作用。在AIM 2 (K99)，我们将表征VP-LHb电路在冲突行为中的作用。在目标3(R00)中，我们将描述 包含DRD1和DRD2的NAC-VP投影在冲突中的作用。在独立阶段，我们还将 描述NAC传入神经元的作用，如内侧前额叶皮质、杏仁核和 室旁丘脑，在冲突行为的控制中。描述控制冲突行为的电路 将有助于指导几种精神疾病的治疗。除了研究计划，这项提案 包括一项培训计划，以促进1)尖端遗传工具方面的专业知识的发展，例如 化学遗传学和纤维光度学.2)数据分析和运行的编程语言 实验；3)为撰写赠款、手稿而进行的科学交流，以及与非 科学家；4)在冷泉港实验室模拟环境中负责任地进行研究。 此外，申请者还将接受他的合作导师关于行为抑郁模型的培训，例如 慢性社会挫败压力和习得性无助，将有必要获得转基因小鼠 Lines，并将接触到病毒操纵和转录的最新分子技术 在合作导师的实验室以电池/电路类型特定的方式进行分析。培训计划的目的是 为研究独立性铺平道路，并增强高度上进的申请者的科学能力。

Project Summary Reward is often present in risky environments, requiring individuals to weigh the benefits of rewards against the associated risks. There are several psychiatric disorders in which patients are unable to choose an appropriate response during risky reward opportunities. Some patients with addiction disorders are driven to seek reward at the expense of high costs and quality of life detriment, whereas some patients with major depression disorder are often too sensitive to punishment and miss out on reward opportunities. Recent research has shown that the lateral habenula (LHb), the ventral pallidum (VP), and the nucleus accumbens (NAc) are key structures that mediate positive and negative motivation, and a circuit involving these structures may govern conflict behavior. In this proposal, we will investigate the role of cell-type specific NAc-VP-LHb circuits in conflict behavior in mice. We will employ a novel conflict task in which thirsty, freely-behaving mice actively choose between seeking water reward or avoiding punishment from a signaled foot-shock by moving to a safety platform. Because the water port and the safety platform are far apart, mice are posed with a conflict of whether to go for reward or to avoid punishment. We will use optogenetic, chemogenetic and photometry imaging approaches to characterize how cell-type specific projections in an NAc-VP-LHb circuit mediate conflict behavior. Aim 1 (K99), we will characterize the role of LHb in conflict behavior. In Aim 2 (K99), we will characterize the role of VP-LHb circuits in conflict behavior. In Aim 3 (R00), we will characterize the role of Drd1 and Drd2-containing NAc-VP projections in conflict. In the independent phase, we will also characterize the role of NAc afferents, such as the medial prefrontal cortex, the amygdala and the paraventricular thalamus, in the control of conflict behavior. Characterizing circuits controlling conflict behavior will help guide treatment for several psychiatric disorders. Additional to the research program, this proposal includes a training plan to foster development of expertise in 1) cutting-edge genetic tools, such as chemogenetics and fiber photometry; 2) programming languages for data analyses and for running experiments; 3) scientific communication for writing for grants, manuscripts and communicating with non- scientists; 4) responsible conduct of research in the stimulating environment of Cold Spring Harbor Laboratory. Moreover, the Applicant will receive training from his co-mentor in behavioral depression models such as chronic social defeat stress and learned helplessness, will have access to the necessary transgenic mouse lines, and will be exposed to the latest molecular techniques on viral manipulations and transcriptomic analyses in a cell/circuit type specific manner at the co-mentor's laboratory. The training plan is tailored to pave a path for research independence and bolster the scientific capabilities of a highly motivated Applicant.