Lateral habenula circuit in reward/conflict mediation

项目摘要 奖励通常存在于危险的环境中，要求个人权衡奖励的好处， 相关风险。有几种精神疾病患者无法选择治疗方法， 在有风险的奖励机会中做出适当的反应。一些成瘾性障碍患者被迫 以高成本和生活质量损害为代价寻求回报，而一些患有重大疾病的患者 抑郁症患者往往对惩罚过于敏感，从而错过奖励机会。最近 研究表明，外侧缰核（LHb）、腹侧苍白球（VP）和延髓核（Nucleus） (NAc)是调节积极和消极动机的关键结构，以及涉及这些结构的回路 可以控制冲突行为。在这个提议中，我们将研究细胞类型特异性NAc-VP-LHb的作用， 小鼠冲突行为中的神经回路我们将采用一种新的冲突任务，其中口渴，自由行为的老鼠 主动选择寻求水的奖励或避免惩罚，从一个信号脚电击移动 安全平台。由于水港和安全平台相距较远，小鼠被摆成一个姿势， 是追求奖赏还是逃避惩罚的冲突我们将使用光遗传学，化学遗传学和 表征NAc-VP-LHb回路中细胞类型特异性投射的光度成像方法 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。在目标2中 (K99)我们将描述VP-LHb回路在冲突行为中的作用。在目标3（R 00）中，我们将描述 Drd 1和Drd 2在冲突中的作用。在独立阶段，我们还将 描述NAc传入的作用，如内侧前额叶皮层，杏仁核和 室旁丘脑，在冲突行为的控制。表征控制冲突行为的电路 将有助于指导几种精神疾病的治疗。除了研究计划外，这项建议 包括一个培训计划，以促进发展1）尖端遗传工具的专业知识，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）科学交流，用于撰写赠款，手稿和与非 科学家; 4）在冷泉港实验室的刺激环境中负责任地进行研究。 此外，申请人将接受其共同导师的行为抑郁模型培训，例如 慢性社会失败压力和习得性无助，将获得必要的转基因小鼠 线，并将接触到病毒操作和转录组学的最新分子技术 在共同指导者的实验室中以细胞/电路类型特定的方式进行分析。培训计划是量身定制的， 为研究独立铺平道路，并加强高度积极性的申请人的科学能力。

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.