Cerebellar Modulation of Frontal Cortical Function

描述（由申请人提供）：发生在自闭症谱系障碍中的小脑浦肯野细胞的发育丧失与不能用单一认知障碍解释的认知缺陷的异质模式相关。小脑浦肯野细胞的简单缺失不太可能直接解释这些无数的认知缺陷。更确切地说，自闭症的本质可能是一种分离综合征，至少部分是由于前额叶皮质（PFC）的小脑调节功能被破坏而导致的。我们有令人兴奋的新数据表明小脑调节PFC多巴胺水平。在这里，我们建议调查的断开假说，小脑的病理结果在前额叶皮层（PFC）的多巴胺能异常，并根据一些核心的神经精神病学自闭症。在目标1中，我们将确定小脑调节PFC中多巴胺释放和亚核中谷氨酸释放的途径，包括小脑到PFC途径，以及这两个结构之间断开的神经化学，电生理，解剖和行为后果。目的1将比较野生型（对照）和失去所有浦肯野细胞的Lurcher小鼠，以确定浦肯野细胞完全丧失对小脑PFC通讯的影响。目标2将研究浦肯野细胞部分丧失的行为和生理后果--这在自闭症患者的大脑中是典型的。使用Lurcher野生型嵌合体与不同的发展损失浦肯野细胞的数量，我们将确定如何神经化学，电生理，解剖和行为指标PFC功能依赖于浦肯野细胞的数量。鉴于在自闭症谱系障碍中发现的小脑神经元数量的减少有据可查，嵌合小鼠的神经化学、电生理、解剖和行为分析提供了一个独特的机会来模拟这些综合征的发育和小脑方面。公共卫生相关性小脑和额叶皮质病变在自闭症和其他发育障碍中常见。这两种异常之间的关系尚不清楚。这个建议提出了一个框架，了解这些看似不同的病理是如何相关的，并提供了一个独特的机会，发现的神经化学，电生理和解剖机制，使小脑可以调节额叶皮质功能，特别是多巴胺和浦肯野细胞的数量。随着这种神经回路内的功能相互作用和适应的细节变得众所周知，这些神经基质和相关的受体机制应该成为治疗与自闭症相关的认知缺陷的新候选者。

DESCRIPTION (provided by applicant): The developmental loss of cerebellar Purkinje cells that occurs in autism spectrum disorders has been associated with a heterogeneous pattern of cognitive deficits that cannot be explained by a unitary cognitive impairment. It is very unlikely that the simple loss of cerebellar Purkinje cells can directly account for these myriad cognitive deficits. Rather, it is likely that autism is, at its essence, a disconnection syndrome that results, at least in part, from a disruption of cerebellar modulation of the prefrontal cortex (PFC). We have exciting new data suggesting that the cerebellum modulates PFC dopamine levels. Here we propose to investigate the disconnection hypothesis that cerebellar pathology results in dopaminergic abnormalities in the prefrontal cortex (PFC) and underlies some of the core neuropsychiatric symptomatology of autism. In Aim 1 we will determine the pathway(s) whereby the cerebellum modulates dopamine release in the PFC and glutamate release in subnuclei comprising the cerebellum to PFC pathways and the neurochemical, electrophysiological, anatomical, and behavioral consequences of a disconnection between these two structures. Aim 1 will compare wildtype (control) and Lurcher mice that loose all Purkinje cells, to determine the consequences of complete loss of Purkinje cells on cerebellar-PFC communication. Aim 2 will investigate the behavioral and physiological consequences of partial loss of Purkinje cells - as typically found in autistic brains. Using Lurcher-wildtype chimeras with varying developmental loss in Purkinje cell numbers we will determine how neurochemical, electrophysiological, anatomical and behavioral indicators of PFC function depend on Purkinje cell number. Given the well documented reductions in cerebellar neuron number that are found in autism spectrum disorders, the neurochemical, electrophysiological, anatomical and behavioral analyses of chimeric mice presents a unique opportunity to model both the developmental and cerebellar aspects of these syndromes. PUBLIC HEALTH RELEVANCE Cerebellar and frontal cortical pathologies have been commonly reported in autism and other developmental disorders. The relationship between these two abnormalities is unknown. This proposal presents a framework for understanding how these seemingly disparate pathologies are related, and provides a unique opportunity for discovery of the neurochemical, electrophysiological and anatomical mechanisms whereby the cerebellum may modulate frontal cortical function, with particular focus on dopamine and Purkinje cell numbers. As the details of the functional interactions and adaptations within this neural circuitry become known, these neural substrates and associated receptor mechanisms should become new candidates for treatment of the cognitive deficits related to autism.