Organization of inhibition in the cerebellar cortex

小脑皮质的抑制组织

• 批准号: 10877237
• 负责人: Jason M Christie
• 金额: $ 57.07万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10877237
• 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 该项目保持与原始应用程序相同。以下是摘要概述。 我们的长期目标是对小脑如何学习改善有一个完整的了解 响应电机错误的移动。攀爬纤维被认为在这一过程中起着至关重要的作用。 因为它们在错误的运动中开火。它们的活性可靠地兴奋浦肯野细胞，产生钙 在共作用的平行纤维输入中，树突中的尖峰可以触发长期的突触可塑性。可塑性 诱导通过改变小脑对感觉运动刺激的反应最终导致纠正行为 可以预测错误的人。重要的是，靶向浦肯野细胞的分子层中间神经元(MLI)的抑制 树突抑制攀升纤维引起的钙信号，相反或‘门控’可塑性诱导。 由于MLI是由运动激活的，这表明运动过程中需要去抑制浦肯野细胞。 学习。由于MLI抑制了其他MLI，它们的相互连接可以支持浦肯野细胞去抑制的电路 在行为过程中。这项提议的目标是研究MLI电路被构造为 支持与环境相关的接触，允许攀爬纤维在 对电机故障的响应。为了实现这一目标，我们将采用多学科方法，使用尖端技术 分子遗传学技术、功能录音、电路图谱和行为分析。第一个目标是， 我们将测试通常支持浦肯野细胞去抑制的MLI到MLI连接的消融是否会影响 攀升纤维在响应运动错误时唤起全面钙信号的能力，以及是否丢失 MLI-MLI回路功能影响小脑依赖的运动学习。在第二个目标中，我们将建立一个 MLI分类，并使用它来调查以前未知的MLI亚型。我们还将使用函数式 录音以测试是否有证据表明MLI网络内存在支持 蒲肯野细胞去抑制专用电路。在第三个目标中，我们将使用解剖追踪来确定 MLI连接体。通过这种方式，我们将确定MLI的独立驱动是否有结构基础 亚型通过它们的传入输入和它们传出输出的细胞类型选择性。完成这些工作 AIMS将导致对分子层的组织逻辑的前所未有的理解。在……里面 特别是，我们希望揭示分子层内的电路是如何控制攀升纤维的诱导的。 中介学习。这些知识不仅有助于发展小脑功能的理论/模型，而且将 还提供了对总体学习过程的洞察。

项目成果

Autonomous Purkinje cell activation instructs bidirectional motor learning through evoked dendritic calcium signaling.

• DOI: 10.1038/s41467-021-22405-8
• 发表时间: 2021-04-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bonnan A;Rowan MMJ;Baker CA;Bolton MM;Christie JM
• 通讯作者: Christie JM

Molecular layer disinhibition unlocks climbing-fiber-instructed motor learning in the cerebellum.

分子层去抑制开启了小脑中攀爬纤维指导的运动学习。

• DOI: 10.1101/2023.08.04.552059
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Zhang,Ke;Yang,Zhen;Gaffield,MichaelA;Gross,GarrettG;Arnold,DonB;Christie,JasonM
• 通讯作者: Christie,JasonM

A deep learning approach to identifying immunogold particles in electron microscopy images.

• DOI: 10.1038/s41598-021-87015-2
• 发表时间: 2021-04-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jerez D;Stuart E;Schmitt K;Guerrero-Given D;Christie JM;Hahn WE;Kamasawa N;Smirnov MS
• 通讯作者: Smirnov MS

Cerebellum encodes and influences the initiation, performance, and termination of discontinuous movements in mice.

• DOI: 10.7554/elife.71464
• 发表时间: 2022-04-22
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Gaffield, Michael A.;Sauerbrei, Britton A.;Christie, Jason M.;Ito-Ishida, Aya
• 通讯作者: Ito-Ishida, Aya

Expression of a Form of Cerebellar Motor Memory Requires Learned Alterations to the Activity of Inhibitory Molecular Layer Interneurons.

小脑运动记忆的某种形式的表达需要对抑制分子层中间神经元的活动进行后天的改变。

• DOI: 10.1523/jneurosci.0731-22.2022
• 发表时间: 2023
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Bonnan,Audrey;Zhang,Ke;Gaffield,MichaelA;Christie,JasonM
• 通讯作者: Christie,JasonM