Acetylcholine and cerebellar dependent motor learning

乙酰胆碱和小脑依赖性运动学习

• 批准号: BB/R017336/1
• 负责人: Richard Apps
• 金额: $ 64.36万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR017336%2F1
• 关键词: Acetylcholine; cerebellar; dependent; motor; learning

Motor learning is fundamental to all new behaviours and includes the improvement of voluntary motor skills with practice and adapting reflex responses to sensory experience (conditioning). Whilst motor learning involves a network of brain regions, the cerebellum is critically involved in both types of motor learning - when the cerebellum is damaged our capacity to learn new voluntary movements and adapt reflex responses is severely impaired. The importance of the cerebellum to brain and behaviour is further emphasized by the fact that it contains over 80% of all neurons in the brain. Text book descriptions of the cerebellum tell us there are two types of input to the cerebellum: mossy fibres and climbing fibres. However, there is an additional class of inputs that have been largely overlooked, which have important modulatory effects on cerebellar circuits and cerebellar-mediated function. These include fibres that use acetylcholine (ACh) as a neurotransmitter and have widespread connections throughout the cerebellum. The primary source of these cholinergic fibres is a brainstem structure called the pedunculopontine nucleus (PPN). Whilst ACh is vital for learning and memory, almost nothing is known about the behavioural significance of cholinergic projections to the cerebellum. This is an important gap in our understanding given the critical role of the cerebellum in motor learning.The current study tests the hypothesis that cholinergic projections from the PPN to the cerebellum regulate neuronal function to control motor learning. An important organizational principle of the cerebellum for understanding its contributions to motor learning is a division into a series of functional units called modules. How individual modules contribute to motor learning remains far from clear, especially those involved in the control of limb movements. The current project uses the modular organization of the cerebellum as a framework to study cholinergic effects on cerebellar circuits during two different types of forelimb-related motor learning: a forelimb reaching task, and a reflex forelimb-flexion conditioning task. The use of these two distinct types of task allows a comprehensive investigation of the roles of the cholinergic projections to the cerebellum during motor learning, in relation to well-defined behavioural outputs. The project is timely because a strong physiological connection between the PPN and cerebellum has only recently been identified, and genetically modified rats to selectively interrogate cholinergic circuits are now available. We will use the combined power of whole animal behavioural and brain slice approaches. At the systems level we will use multichannel electrophysiological recording methods to examine neuronal population activity and spike trains of individual neurons, and interventionist methods (pharmacological/optogenetic) to understand how PPN and cerebellum orchestrate their activity during motor learning. At the cellular level we will use genetic approaches to selectively stimulate PPN release of ACh to determine how this neuromodulator controls neuronal and synaptic function at the cellular level. Collectively these approaches will provide novel insights into the cellular mechanisms and circuit basis of motor learning. Choice of experimental model: cerebellar network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been well characterized in rats and that correlate to human motor learning. Overall, the results of our study aim to provide a mechanistic understanding of how neural circuits within the brain give rise to our ability to learn new movements.

运动学习是所有新行为的基础，包括通过练习和适应感官体验的反射反应（条件反射）来提高自主运动技能。虽然运动学习涉及大脑区域的网络，但小脑在这两种类型的运动学习中都有重要作用-当小脑受损时，我们学习新的自主运动和适应反射反应的能力严重受损。小脑对大脑和行为的重要性进一步强调了它包含大脑中超过80%的神经元。教科书上对小脑的描述告诉我们，小脑有两种类型的输入：苔藓纤维和攀爬纤维。然而，还有一类输入在很大程度上被忽视了，它们对小脑回路和小脑介导的功能具有重要的调节作用。这些包括使用乙酰胆碱（ACh）作为神经递质的纤维，并且在整个小脑中具有广泛的连接。这些胆碱能纤维的主要来源是脑干结构，称为脚桥核（PPN）。虽然乙酰胆碱对学习和记忆至关重要，但对小脑胆碱能投射的行为意义几乎一无所知。这是一个重要的差距，在我们的理解，小脑在运动learning.The目前的研究测试的假设，胆碱能预测从PPN小脑调节神经元功能，以控制运动learning. The的关键作用。要了解小脑对运动学习的贡献，小脑的一个重要组织原则是分为一系列称为模块的功能单元。各个模块如何促进运动学习仍然很不清楚，特别是那些涉及肢体运动控制的模块。目前的项目使用小脑的模块化组织作为一个框架，研究胆碱能对小脑电路在两种不同类型的前肢相关的运动学习：前肢达到任务，反射前肢屈曲条件反射任务。这两种不同类型的任务的使用允许一个全面的调查的胆碱能投射到小脑在运动学习的作用，在定义明确的行为输出。该项目是及时的，因为PPN和小脑之间的强烈生理联系直到最近才被确定，并且现在可以选择性地询问胆碱能回路的转基因大鼠。我们将使用整个动物行为和大脑切片方法的综合力量。在系统水平上，我们将使用多通道电生理记录方法来检查神经元群体活动和单个神经元的尖峰序列，以及干预方法（药理学/光遗传学）来了解PPN和小脑如何在运动学习过程中协调它们的活动。在细胞水平上，我们将使用遗传方法来选择性地刺激PPN释放ACh，以确定这种神经调节剂如何在细胞水平上控制神经元和突触功能。总的来说，这些方法将为运动学习的细胞机制和电路基础提供新的见解。实验模型的选择：小脑网络结构和连接模式在包括人类在内的哺乳动物物种中高度保守。然而，大鼠是首选的实验动物，因为我们对基本神经解剖学和生理学的理解在这个物种中是最完整的。重要的是，我们的实验将包括在行为情况下的神经网络相互作用的研究，这些行为情况在大鼠中得到了很好的表征，并与人类运动学习相关。 总的来说，我们的研究结果旨在提供一种机制性的理解，即大脑中的神经回路如何提高我们学习新动作的能力。

项目成果

Cerebellar Prediction and Feeding Behaviour.

• DOI: 10.1007/s12311-022-01476-3
• 发表时间: 2023-10
• 期刊: Cerebellum (London, England)

The role of cerebellar acetylcholine receptors in motor behaviour

小脑乙酰胆碱受体在运动行为中的作用

• 发表时间: 2020
• 作者: Pickford J

Encoding of motor and non-motor information in cerebellar-prefrontal cortical circuits

小脑前额皮质回路中运动和非运动信息的编码

• 发表时间: 2019
• 作者: J Pickford

Muscarinic Receptor Modulation of the Cerebellar Interpositus Nucleus In Vitro.

• DOI: 10.1007/s11064-018-2613-9
• 发表时间: 2019-03
• 期刊: Neurochemical research
• 影响因子: 4.4
• 作者: Pickford J;Apps R;Bashir ZI
• 通讯作者: Bashir ZI

Trials for Cerebellar Ataxias - From Cellular Models to Human Therapies

小脑性共济失调试验 - 从细胞模型到人类疗法

• DOI: 10.1007/978-3-031-24345-5_2
• 发表时间: 2023
• 作者: Pickford J