Organization of inhibition in the cerebellar cortex

小脑皮质的抑制组织

• 批准号: 10349928
• 负责人: Jason M Christie
• 金额: $ 122.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349928
• 关键词: Organization; inhibition; cerebellar; cortex

Project Summary The project remains the same as the original application. Below is a summary overview. Our long-term goal is to generate a complete understanding of how the cerebellum learns to improve movement in response to motor errors. Climbing fibers are thought to play an essential role in this process because they fire during erroneous movement. Their activity reliably excites Purkinje cells, eliciting calcium spikes in their dendrites that can trigger long-term synaptic plasticity at coactive parallel fiber inputs. Plasticity induction ultimately leads to corrective behavior by altering the cerebellum's response to sensorimotor stimuli that predict mistakes. Importantly, inhibition from molecular layer interneurons (MLIs) that target Purkinje cell dendrites suppresses climbing-fiber-evoked calcium signaling, opposing or `gating' plasticity induction. Because MLIs are activated by movement, this suggests Purkinje cell disinhibition is required during motor learning. As MLIs inhibit other MLIs, their interconnections could support a circuit for Purkinje cell disinhibition during behavior. The objective of this proposal is to examine the possibility that MLI circuits are structured to support a context-dependent engagement that allows climbing fibers to instruct plasticity and learning in response to motor errors. To accomplish this, we will employ a multidisciplinary approach using cutting-edge molecular-genetic techniques, functional recordings, circuit mapping, and behavioral analysis. In the first aim, we will test whether ablating MLI-to-MLI connections that normally support Purkinje cell disinhibition affect the ability of climbing fibers to evoke full-blown calcium signals in response to motor errors, and whether loss of MLI-MLI circuit function affects cerebellar-dependent motor learning. In the second aim, we will establish an MLI taxonomy and use it to survey for previously unknown MLI subtypes. We will also use functional recordings to test whether there is evidence for bias connectivity within the MLI network that supports a dedicated circuit for Purkinje cell disinhibition. In the third aim, we will use anatomical tracing to ascertain the MLI connectome. In this way we will determine if there is a structural basis for the independent actuation of MLI subtypes through their afferent inputs and the cell-type selectivity of their efferent outputs. Completion of these aims will lead to an unprecedented understanding of the organizational logic of the molecular layer. In particular, we expect to reveal how circuits within the molecular layer control the induction of climbing-fiber- mediated learning. This knowledge will not only help develop theories/models of cerebellum function but will also provide insight into the processes underlying learning in general.

项目摘要 该项目与原始应用程序保持不变。以下是摘要概述。 我们的长期目标是对小脑学习如何改善的方式完全了解 响应电动机错误的运动。人们认为攀爬纤维在此过程中起着至关重要的作用 因为他们在错误的运动中发射。它们的活性可靠地激发了Purkinje细胞，引起钙 其树突中的尖峰可以触发同型平行纤维输入的长期突触可塑性。可塑性 诱导最终通过改变小脑对感觉运动刺激的反应来导致纠正行为 预测错误。重要的是，靶向Purkinje细胞的分子层中间神经元（MLI）的抑制作用 树突抑制攀岩纤维诱发的钙信号，相反或“门控塑性诱导”。 由于MLI被运动激活，这表明在电机期间需要purkinje细胞抑制作用 学习。由于MLI抑制其他MLI，它们的互连可以支持Purkinje细胞抑制作用的电路 在行为期间。该提案的目的是检查MLI电路的结构可能性 支持依赖上下文的参与度，允许攀爬纤维指导可塑性和学习 对电机错误的响应。为此，我们将使用前沿采用多学科的方法 分子遗传技术，功能记录，电路映射和行为分析。在第一个目标中 我们将测试通常支持Purkinje细胞抑制作用的MLI到MLI连接是否会影响 攀岩纤维能够响应电动机错误以及是否损失来唤起成熟的钙信号 MLI-MLI电路功能会影响小脑依赖性运动学习。在第二个目标中，我们将建立一个 MLI分类法并使用它来调查以前未知的MLI亚型。我们还将使用功能 记录以测试MLI网络中是否有偏见连接的证据支持A Purkinje细胞抑制作用的专用电路。在第三个目的中，我们将使用解剖学跟踪来确定 MLI Connectome。通过这种方式，我们将确定MLI独立致动的结构基础是否存在 亚型通过其传入输入以及其传出输出的细胞类型选择性。这些完成 目的将导致对分子层的组织逻辑的前所未有的理解。在 特别是，我们期望揭示分子层中的电路如何控制攀爬纤维的诱导 介导的学习。这些知识不仅可以帮助发展小脑功能的理论/模型 还可以深入了解一般学习的过程。