Defining cell types that control action selection and execution

项目总结/摘要 大脑的一项基本任务是选择下一步做什么，而选择适当的 行为和抑制不适当的行为被认为是包括精神分裂症在内的疾病的基础， 成瘾和亨廷顿病。大脑如何权衡可用的行动来选择和执行最多 adaptive不能理解。在典型模型中，效应器结构，如上级丘（SC）， 不断地准备产生行为，但被基底神经元的紧张性活性GABA能神经元抑制。 神经节（BG）输出核黑质网状部（SNr）和内部苍白球;在动作之前， 抑制该动作的BG输出神经元的特定子集暂停放电以"释放"其效应器通路。 然而，几项研究表明，SNr含有多种GABA能抑制细胞类型， 有些神经元只有相位性活动，而紧张性和相位性抑制性SNr神经元都可以会聚在同一个神经元上。 这些细胞类型混杂在SNr中，这阻碍了我们的努力。 应用现代神经科学的遗传工具来破译它们的会聚相位和紧张性抑制 信号影响下游神经处理以控制行为选择和执行。为了克服这一点 障碍，我的实验室已经开发出选择性表达基因工具的方法，无论是相位或紧张性SNr 神经元在这里，我建议应用我们的方法，以揭示如何阶段性和紧张性抑制BG亚型 协调行为首先，我们将测试这样一个假设，即相位SNr神经元既编码行为选择， 并通过记录他们在行为过程中的活动来执行。第二，我们将测试假设， 抑制性神经元使用有针对性的操纵来塑造所选行为的选择和执行。 第三，为了理解这些相位型和强直型之间生理差异的转录基础， 我们将在单细胞测序中使用新的条形码方法来定义两者的遗传特性。 总的来说，这些研究将提供一个全面的画像，如何阶段性和紧张性抑制BG细胞 类型协调行为选择和执行。这些研究的结果可能有助于我们理解 病因学和导致新的治疗方法的条件，包括成瘾，精神分裂症，帕金森氏症， 亨廷顿氏病。

PROJECT SUMMARY/ABSTRACT A fundamental task of the brain is to choose what to do next, and an impaired ability to select appropriate behaviors and repress inappropriate actions is thought to underlie conditions including schizophrenia, addiction, and Huntington's disease. How the brain weighs available actions to choose and execute the most adaptive is not understood. In the canonical model, effector structures such as the superior colliculus (SC) are constantly poised to generate behaviors, but are repressed by tonically active GABAergic neurons of the basal ganglia (BG) output nuclei substantia nigra pars reticulata (SNr) and internal globus pallidus; before an action, the specific subset of BG output neurons inhibiting that action pause firing to “release” its effector pathway. However, several studies have revealed that SNr harbors multiple GABAergic inhibitory cell types of which some are only phasically active, and both tonic and phasic inhibitory SNr neurons can converge on the same target neurons in structures such as SC. These cell types are intermingled in SNr, which has hindered efforts to apply the genetic tools of modern neuroscience to decipher how their convergent phasic and tonic inhibitory signals influence downstream neural processing to control behavioral choice and execution. To surmount this obstacle, my lab has developed approaches to selectively express genetic tools in either phasic or tonic SNr neurons. Here I propose to apply our approach to reveal how phasic and tonic inhibitory BG subtypes coordinate behavior. First, we will test the hypothesis that phasic SNr neurons encode both behavioral choice and execution by recording their activity during behavior. Second, we will test the hypothesis that phasic inhibitory neurons shape both choice and execution of the chosen behavior using targeted manipulations. Third, to understand the transcriptional basis of physiologic differences between these phasic and tonic types, we will define the genetic identities of both using a novel barcoding approach in single-cell sequencing. Collectively, these studies will provide a comprehensive portrait of how phasic and tonic inhibitory BG cell types coordinate behavioral choice and execution. The findings from these studies may help us to understand the etiology of and lead to new treatments for conditions including addiction, schizophrenia, Parkinson's, and Huntington's disease.