Models of the Cerebellar Purkinje Cell and Cortex

奖项摘要150年来，小脑一直被认为主要参与调节运动。此外，大多数小脑运动控制的功能模型都是基于对这一结构的解剖学和生理学组织的百年了解。然而，在过去的10年里，越来越多的证据表明，小脑可能参与的不仅仅是运动控制。与这种对小脑整体功能的思考发生的戏剧性变化相平行的是，最近的实验结果也表明，对小脑回路组织的标准功能解释可能也需要重大修改。具体地说，大多数小脑模型和理论都是基于这样的假设，即为每个小脑浦肯野细胞(哺乳动物神经系统中最大的兴奋性突触会聚)提供的150,000个平行纤维兴奋性突触输入直接驱动浦肯野细胞动作电位的产生，即它们的输出。积累的实验和模型证据表明，情况并非如此。这里支持的研究结合了现实的计算机建模技术、电生理学和解剖学，以更好地了解这种大规模突触会聚对大鼠浦肯野细胞的明显缺乏直接兴奋影响。特别是，这项研究集中在小脑皮质抑制神经元所起的功能作用，这些神经元在当前的小脑功能理论中被很大程度上忽视了。被检验的具体假设是，小脑所谓分子层的抑制动态地抵消平行纤维的兴奋效应，将平行纤维/分子层抑制系统转变为调制影响，而不是直接驱动影响。这一结果有望为我们快速扩展和进化对小脑皮质网络功能组织的理解提供新的基础，并相应地为研究小脑在哺乳动物大脑中的一般作用提供新的基础。这项研究还将为通常在科学界代表性较低的群体中的个人提供研究参与。

Award AbstractFor 150 years the cerebellum has been assumed to be primarily involved in regulating movement. In addition, most functional models of cerebellar movement control are based on a 100 year old understanding of the anatomical and physiological organization of this structure. Over the last 10 years, however, evidence has accumulated that the cerebellum may be involved in much more than just movement control. Paralleling this rather dramatic change in thinking about overall cerebellar function, recent experimental results also suggest that the standard functional interpretation of the organization of cerebellar circuits may also require significant revision. Specifically, most cerebellar models and theories are based on the assumption that the 150,000 parallel fiber excitatory synaptic inputs provided each cerebellar Purkinje cell (the largest excitatory synaptic convergence for any cell in the mammalian nervous system) directly drive the generation of Purkinje cell action potentials, i.e., their output. Accumulating experimental and modeling evidence suggests that this is not the case. The research supported here uses a combination of realistic computer modeling techniques, electrophysiology, and anatomy to better understand the apparent lack of direct excitatory influence of this massive synaptic convergence on Purkinje cells in the rat. In particular, this research is focused on the functional role played by cerebellar cortical inhibitory neurons, which have largely been overlooked, in current theories of cerebellar function. The specific hypothesis tested is that inhibition in the so-called molecular layer of the cerebellum dynamically counteracts the excitatory effect of the parallel fibers, turning the parallel fiber / molecular layer inhibitory system into a modulatory, rather than a direct driving, influence. The results are expected to provide a new foundation for our rapidly expanding and evolving understanding of the functional organization of the cerebellar cortical network, and accordingly a new foundation for considering the general role of the cerebellum in the mammalian brain. The research will also provide research involvement for individuals from groups typically underrepresented in science.