Brainstem circuits of corticospinal neurons

项目总结 皮质脊髓轴突投射对哺乳动物的运动控制至关重要。它们的长度和复杂性使得 他们容易受到包括脑血管疾病在内的各种神经疾病过程的影响 疾病、脱髓鞘疾病、肌萎缩侧索硬化症、脊髓损伤等等。皮质脊髓研究自然有 重点放在皮质和脊髓机制上。然而，与其他类型的锥体一样，皮质脊髓轴突 束神经元，可以将分支发送到中脑、脑桥和延髓，沿着这条路到达脊髓。这个 皮质脊髓轴突分支至脑干靶点的解剖学“项目组”尚未得到系统的研究 调查过了。对突触“连接体”的了解就更少了；也就是说，由 皮质脊髓传入不同脑干核团中的突触后神经元。阐明大脑皮层的脑干回路 皮质脊髓轴突对于理解哺乳动物运动控制的细胞基础将是重要的。为 例如，很可能有一些迄今尚未识别的皮质脊髓神经元亚型，通过分化 脑干靶点的神经支配，介导特定的感觉运动、神经调节或其他基本功能 用于运动协调和控制。我们提出了一个双管齐下的方法来研究脑干分支。 以及小鼠皮质脊髓轴突的环路。在目标1中，我们将使用高通量的分子条形码 技术，MAPseq，以表征皮质脊髓向脑干投射的多样性和复杂性， 具有单轴分辨率和大规模采样的特点。在目标2中，我们将使用光遗传学、电生理学 成像和病毒标记工具，以表征这些回路中特定细胞类型的突触连接。这个 皮质脊髓轴突脑干分支的投射和连接将在以下两个方面进行广泛的调查 区域(中脑、桥脑、延髓)，并在特定类型的水平上更有针对性地进行分析 关键核团中的投射神经元，包括那些与感觉运动、神经调节等有关的神经元 系统(网状、桥状、楔状、蓝斑等)。这项以发现为导向的研究的结果 该计划将为未来以假说为导向的研究奠定基础--从机械上 特定细胞类型及其突触连接的重要水平--皮质脊髓的脑干回路 神经元对哺乳动物的运动功能有贡献。

PROJECT SUMMARY Corticospinal axonal projections are critical for mammalian motor control. Their length and complexity makes them vulnerable to an exceptionally wide range of neurological disease processes including cerebrovascular disorders, demyelinating diseases, ALS, spinal cord injury, and more. Corticospinal research has naturally focused on cortical and spinal mechanisms. However, corticospinal axons, like those of other types of pyramidal tract neurons, can send branches to the midbrain, pons, and medulla along the way to the spinal cord. The anatomical “projectome” of corticospinal axonal branching to brainstem targets has not been systematically investigated. Even less is known about the synaptic “connectome”; i.e., the cellular circuits formed by corticospinal input to postsynaptic neurons in various brainstem nuclei. Elucidating the brainstem circuits of corticospinal axons will be important for understanding the cellular basis of mammalian motor control. For example, there very likely are as-yet unrecognized subtypes of corticospinal neurons that, through differential innervation of brainstem targets, mediate specific sensorimotor, neuromodulatory, or other functions essential for motor coordination and control. We propose a two-pronged approach to investigate the brainstem branches and circuits of corticospinal axons in the mouse. In Aim 1, we will use a high-throughput molecular barcoding technique, MAPseq, to characterize the diversity and complexity of corticospinal projections to the brainstem, with single-axon resolution and large-scale sampling. In Aim 2, we will use optogenetic, electrophysiological, imaging, and viral labeling tools to characterize the cell-type-specific synaptic connectivity in these circuits. The projections and connections of corticospinal axons’ brainstem branches will be both broadly surveyed across regions (midbrain, pons, medulla) and analyzed in a more focused manner at the level of specific types of projection neurons in key nuclei, including those associated with sensorimotor, neuromodulatory, and other systems (reticular, pontine, cuneate, locus coeruleus, and more). Results from this discovery-oriented research program will lay the groundwork for future hypothesis-oriented studies to investigate – at the mechanistically important level of specific cell types and their synaptic connectivity – how the brainstem circuits of corticospinal neurons contribute to mammalian motor function.