Cerebellar Modulation of Frontal Cortical Function

描述（由申请人提供）：自闭症谱系障碍中发生的小脑浦肯野细胞发育损失与认知缺陷的异质模式有关，而这种认知缺陷不能用单一的认知障碍来解释。小脑浦肯野细胞的简单丧失不太可能直接解释这些无数的认知缺陷。相反，自闭症本质上很可能是一种脱节综合症，其至少部分是由于前额皮质（PFC）的小脑调节破坏造成的。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，我们建议研究断层假说，即小脑病理导致前额皮质（PFC）多巴胺能异常，并成为自闭症一些核心神经精神症状的基础。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 途径以及这两种结构之间断开的神经化学、电生理学、解剖学和行为后果。目标 1 将比较野生型（对照）小鼠和失去所有浦肯野细胞的 Lurcher 小鼠，以确定浦肯野细胞完全缺失对小脑 - PFC 通讯的影响。目标 2 将研究浦肯野细胞部分缺失（通常在自闭症大脑中发现）的行为和生理后果。使用具有不同浦肯野细胞数量发育损失的 Lurcher 野生型嵌合体，我们将确定 PFC 功能的神经化学、电生理学、解剖学和行为指标如何依赖于浦肯野细胞数量。鉴于自闭症谱系障碍中发现的小脑神经元数量减少的充分记录，嵌合小鼠的神经化学、电生理学、解剖学和行为分析为模拟这些综合征的发育和小脑方面提供了独特的机会。

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.