Role of thalamic modulation in motor learning

项目总结 学习和执行运动技能是大脑的重要功能，涉及到 多个脑区。传统上，运动皮质(MCtx)、基底节(BG)和小脑(CB) 一直被认为是大脑中关键的运动控制区，这些区域内的可塑性被认为是 支持运动学习。此外，神经调节，如来自蓝斑的肾上腺素能神经元 (LC)，对于正确的行为和学习至关重要。尽管这些地区在控制中发挥着关键作用 运动及其在运动障碍中的意义，我们才刚刚开始了解运动 来自这些区域的信号相互作用。从解剖学上讲，丘脑是一个共同的靶子 Mctx、BG和CB的结构，但传统上，丘脑一直被视为一个被动中继站。 然而，有新的证据表明，丘脑可以在功能上整合和调节这些不同的 电机信号。丘脑神经元如何对运动输入做出反应，运动丘脑在运动学习中的作用， 肾上腺素能信号如何调节丘脑活动在很大程度上还没有定论。我的中心假设是 运动丘脑是来自MCtx、BG和CB的运动信号的汇合点，以及 来自LC的神经调节性输入，使其能够在功能上整合这些输入来控制运动和 促进运动学习。我建议使用活体脑深部成像和新型荧光技术相结合 执行运动任务的小鼠的细胞内信号传感器，以及切片电生理学，以 测量运动中丘脑的活动，并确定这种活动是如何被 来自LC的肾上腺素能输入。这些方法将使我能够定义运动丘脑的输入并测量 丘脑在运动和运动学习中的活动(目标1)，确定运动丘脑的功能作用 及其在运动控制中的输入(目标2)，并确定肾上腺素能信号如何调节丘脑活动 在运动学习期间(目标3)。这项研究的结果不仅将阐明运动丘脑在 运动控制和运动学习，也提供了对肾上腺素能神经调节的理解 会影响行为过程中的丘脑活动。这一点至关重要，因为异常的丘脑活动和 肾上腺素能信号受阻是运动性疾病的特征。这项研究中提出的实验 研究将跨越该奖项的指导K99阶段和独立的R00阶段，重点是K99阶段 运动学习中运动丘脑的活动和作用及R00阶段的定位 了解传入丘脑的肾上腺素能如何调节运动信号。我提出的培训计划建立了 关于我在体内双光子成像和小鼠行为方面的经验，并将在切片方面增加培训 电生理学。此外，我的专家指导团队还将为我的职业发展提供指导 目标是在一家研究机构作为独立调查员开始成功的职业生涯。

PROJECT SUMMARY Learning and executing motor skills are crucial functions of the brain and involve the coordinated activity of multiple brain regions. Traditionally, the motor cortex (MCtx), the basal ganglia (BG), and the cerebellum (CB) have been considered key motor control regions of the brain, and plasticity within these regions are known to support motor learning. In addition, neuromodulation, such as from adrenergic neurons in the locus coeruleus (LC), is critical for proper behavior and learning. Despite the key role these regions play in controlling movements and their implication in movement disorders, we are only beginning to understand how motor signals from these regions interact with each other. Anatomically, the thalamus serves as a common target structure for MCtx, BG, and CB, yet conventionally, the thalamus has been viewed as a passive relay station. However, there is emerging evidence that the thalamus can functionally integrate and modulate these diverse motor signals. How thalamic neurons respond to motor inputs, the role of motor thalamus in motor learning, and how adrenergic signaling modulates thalamic activity are largely undefined. My central hypothesis is that the motor thalamus serves as a point of convergence for motor signals from MCtx, BG, and CB, as well as neuromodulatory input from LC, allowing it to functionally integrate these inputs to control movements and promote motor learning. I propose to use a combination of in vivo deep-brain imaging and novel fluorescent sensors for intracellular signaling in mice performing motor tasks, as well as slice electrophysiology, to measure the activity of motor thalamus during movement and determine how such activity is modulated by adrenergic input from LC. These approaches will allow me to define the inputs to motor thalamus and measure thalamic activity during movement and motor learning (Aim 1), determine the functional role of motor thalamus and its inputs in motor control (Aim 2), and determine how adrenergic signaling modulates thalamic activity during motor learning (Aim 3). Results from this study will not only clarify the role of the motor thalamus in motor control and motor learning but also provide an understanding of how adrenergic neuromodulation influences thalamic activity during behavior. This is of critical importance, as abnormal thalamic activity and disrupted adrenergic signaling are characteristic features of motor diseases. The experiments proposed in this study will span the mentored K99 and independent R00 phase of this award, with the K99 phase being focused on defining the activity and role of motor thalamus during motor learning and the R00 phase focused on understanding how adrenergic input to the thalamus modulates motor signals. My proposed training plan builds on my experience in two-photon in vivo imaging and mouse behaviors and will add training in slice electrophysiology. In addition, my expert mentoring team will also provide guidance in my career development with the goal of launching a successful career as independent investigator at a research institution.