Defining cell types that control action selection and execution

项目摘要/摘要 大脑的一个基本任务是选择下一步做什么，以及选择适当的 行为和抑制不当行为被认为是包括精神分裂症在内的疾病的基础， 上瘾和亨廷顿氏症。大脑如何权衡选择和执行最多的可用行动 适应性是不被理解的。在正则模型中，上丘(SC)等效应器结构 持续稳定地产生行为，但受到基底核强直活动的GABA能神经元的抑制 神经节(BG)输出黑质网状部(SNR)和苍白球内侧核；动作前， BG的特定亚群输出神经元抑制这一动作，暂停放电，以“释放”其效应器通路。 然而，一些研究表明，SNR含有多种类型的GABA能抑制细胞 有些神经元只是相活动的，强直和相抑制SNR神经元可以汇聚在同一个神经元上。 靶向SC等结构中的神经元。这些细胞类型在SNR中混杂在一起，这阻碍了努力 应用现代神经科学的遗传工具来破译它们的收敛时相和紧张性抑制 信号影响下游神经处理，以控制行为的选择和执行。要克服这一点 为了克服障碍，我的实验室已经开发出在相或紧张期SNR中选择性表达遗传工具的方法 神经元。在这里，我建议应用我们的方法来揭示相性和紧张性抑制性BG亚型 协调行为。首先，我们将检验这一假设，即相SNR神经元编码两种行为选择 并通过记录他们在行为过程中的活动来执行。第二，我们将检验假设阶段 抑制性神经元使用有针对性的操作来塑造对所选行为的选择和执行。 第三，为了了解这些时相类型和主音类型之间的生理差异的转录基础， 我们将在单细胞测序中使用一种新的条形码方法来定义两者的遗传特性。 总而言之，这些研究将全面描述时相和紧张性抑制性BG细胞是如何 类型协调行为选择和执行。这些研究的发现可能有助于我们理解 成瘾、精神分裂症、帕金森氏症等疾病的病因和新的治疗方法 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.