Models of the Cerebellar Purkinje Cell and Cortex

150年来，人们一直认为小脑主要参与调节运动。此外，大多数小脑运动控制的功能模型都是基于对该结构的解剖和生理组织的100年前的理解。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。与对小脑整体功能的这种相当戏剧性的改变并行，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进行重大修订。具体来说，大多数小脑模型和理论都是基于这样的假设，即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汇聚）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、电生理学和解剖学来更好地理解这种大规模突触聚合对大鼠浦肯野细胞明显缺乏直接兴奋影响。本研究特别关注小脑皮质抑制性神经元的功能作用，这在目前的小脑功能理论中很大程度上被忽视。经过测试的具体假设是，所谓的小脑分子层的抑制动态抵消了平行纤维的兴奋作用，将平行纤维/分子层抑制系统转变为调节性影响，而不是直接驱动影响。这些结果有望为我们对小脑皮质网络的功能组织的快速扩展和进化的理解提供新的基础，从而为考虑小脑在哺乳动物大脑中的一般作用提供新的基础。这项研究还将为来自通常在科学中代表性不足的群体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.