Striatal substrates regulating sensory-guided and memory-guided behaviors

纹状体基质调节感觉引导和记忆引导行为

• 批准号: 9760431
• 负责人: Scott Steven Bolkan
• 金额: $ 6.16万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760431
• 关键词: ADORA2A gene; Acceleration; Address; Animals; Area; Basal Ganglia; Behavior; Behavioral; Biological Assay; Brain; Brain imaging; Calcium; Cell Nucleus; Cephalic; Chronic; Code; Cognitive; Cognitive deficits; Computational Technique; Corpus striatum structure; Cues; Data; Decision Making; Dependence; Disease; Environment; Exhibits; Functional disorder; Generations; Human; Image; Impaired cognition; Impairment; Lampreys; Left; Maps; Measures; Memory; Modeling; Modernization; Motor; Motor output; Movement; Mus; Neurons; Optics; Outcome; Output; Parkinson Disease; Pathway interactions; Patients; Performance; Photons; Process; Psychometrics; Psychophysics; Reporting; Rewards; Schizophrenia; Sensory; Short-Term Memory; Side; Speed; Stimulus; Surveys; Tactile; Training; Transgenic Mice; Visual; arm; base; calcium indicator; cell type; cognitive function; cognitive process; exhaustion; experimental study; improved; insight; kinematics; motor deficit; motor impairment; neural circuit; neural correlate; neural patterning; novel; operation; optogenetics; relating to nervous system; sensory integration; three photon microscopy; tool; virtual; virtual reality

STRIATAL SUBSTRATES REGULATING SENSORY-GUIDED AND MEMORY-GUIDED BEHAVIORS Abstract Decision-making requires the continual integration of sensory evidence for and against alternative options, as well as the selection and execution of a motor output aimed at achieving a desired outcome. Activity in mutually antagonistic direct- and indirect-pathways of the striatum has long been hypothesized to regulate the selection of actions by exerting opposing effects on behavior. While activations of direct- and indirect-pathway neurons have recently been shown to produce opposing behaviors, it remains fundamentally unresolved whether endogenous activity in striatal pathways contribute directly to the generation of a motor output, or if they participate in cognitive processes influencing the decision towards a motor output. To address this question we will utilize a suite of modern neural circuit tools in mice performing two virtual reality (VR)-based navigation tasks that have identical motor requirements, but differ in their dependence on sensory- versus memory-guided behavior. Using this powerful behavioral approach we will carefully disambiguate simple motor processes from those involving the accumulation of evidence, a highly quantitative assay of working memory based decision-making. We further propose to exploit this unified task framework towards a comprehensive survey of the causal relationships and neural dynamics underlying sensory-guided motor output and memory- guided decisions in direct- and indirect-pathways across two striatal sub-regions (dorsomedial, DMS, or dorsolateral, DLS). First, using cell-type specific, optogenetic inhibition we will causally determine whether each pathway in DMS or DLS is necessary for sensory- and memory-guided motor outputs. Employing temporally limited, sub-trial inhibition we will further determine precisely when each pathway in each striatal sub-region supports memory-guided motor output. Finally, utilizing state-of-the-art 3-photon imaging for deep brain areas, we will examine how activity in DMS and DLS direct- and indirect-pathway neurons encodes information related to motor and cognitive operations supporting decision-making in the two tasks. Importantly, our task settings provide tremendous power to closely readout and quantify elemental motor and cognitive operations, allowing us to precisely measure which aspect(s) of motor output and decision-making depend on each striatal pathway and sub-region, and how dynamic patterns of neural activity map onto component processes sub-serving these behaviors. Our experiments will therefore provide a detailed and quantitative account of the causal mechanisms and neural correlates supporting sensory- and memory-guided behavior in the direct- and indirect- pathways of the DMS and DLS. Our findings promise to generate novel insight into basic motor and cognitive functions of striatal cell-types across striatal domains, an endeavor with tremendous significance for improving understanding of human disorders such as schizophrenia and Parkinson's disease, which exhibit divergent cognitive and motor deficits while sharing a core dysfunction in striatal circuitry.

调节感觉引导和记忆引导行为的纹状体基质 摘要 决策需要不断整合支持和反对替代选择的感官证据，如 以及旨在实现期望结果的马达输出的选择和执行。中的活动 长期以来，纹状体相互拮抗的直接和间接通路一直被认为是为了调节 通过对行为施加相反的影响来选择动作。而直接和间接通路的激活 神经元最近被证明会产生相反的行为，但从根本上说，它仍然没有得到解决 纹状体通路中的内源性活动是否直接有助于运动输出的产生，或者是否 他们参与认知过程，影响对运动输出的决定。要解决这个问题 问题我们将利用一套现代神经电路工具在小鼠身上执行两个基于虚拟现实(VR)的 导航任务具有相同的运动要求，但对感觉的依赖不同-与 记忆引导的行为。使用这一强大的行为方法，我们将仔细地消除简单运动的歧义 从那些涉及证据积累的过程中，高度定量地分析工作记忆 以决策为基础。我们还建议利用这一统一的任务框架来实现全面的 关于感觉引导的运动输出和记忆背后的因果关系和神经动力学的研究 在两个纹状体亚区(背内侧、DMS或 背外侧，DLS)。首先，利用细胞类型特异性的光遗传抑制，我们将因果地确定 DMS或DLS中的每一条通路都是感觉和记忆引导的运动输出所必需的。用人 我们将进一步准确地确定每条纹状体中每条通路的时间 子区域支持记忆引导电机输出。最后，利用最先进的三光子成像技术 大脑区域，我们将研究DMS和DLS直接和间接通路神经元的活动如何编码 在这两个任务中，与运动和认知操作相关的信息支持决策。重要的是 我们的任务设置提供了强大的能力，可以近距离读出和量化基本运动和认知 操作，使我们能够精确地测量电机输出和决策的哪个方面(S) 每条纹状体通路和子区域，以及神经活动的动态模式如何映射到组件 子服务于这些行为的进程。因此，我们的实验将提供详细和定量的 对支持感觉和记忆引导行为的因果机制和神经关联的阐述 DMS和DLS的直接途径和间接途径。我们的发现有望产生新的见解 纹状体细胞类型跨越纹状体领域的基本运动和认知功能，这是一个巨大的努力 对提高对精神分裂症和帕金森氏症等人类疾病的认识的意义， 他们表现出不同的认知和运动障碍，同时共享纹状体回路的核心功能障碍。