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的发育丧失与一种不同的认知障碍模式有关，这不能用单一的认知障碍来解释。简单的小脑浦肯野细胞的丧失不太可能直接解释这些无数的认知缺陷。相反，自闭症在本质上很可能是一种脱节综合症，至少部分原因是小脑对前额叶皮质(PFC)调制的中断。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，我们建议调查分离假说，即小脑病理导致前额叶皮质(PFC)的多巴胺能异常，并构成自闭症的一些核心神经精神症状学基础。在目标1中，我们将确定小脑调节前额叶多巴胺释放和亚核谷氨酸释放的途径(S)，包括小脑到前额叶通路的亚核以及这两个结构之间断开的神经化学、电生理、解剖学和行为学后果。目的1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--这是自闭症大脑中常见的现象。利用浦肯野细胞数量不同发育损失的Lurcher-Wild型嵌合体，我们将确定PFC功能的神经化学、电生理、解剖学和行为学指标如何依赖浦肯野细胞数量。鉴于在自闭症谱系障碍中发现的小脑神经元数量减少的充分证据，嵌合体小鼠的神经化学、电生理、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一个独特的机会。与公共卫生相关的小脑和额叶皮质病理学在自闭症和其他发育障碍中经常被报道。这两种异常之间的关系尚不清楚。这一建议为理解这些看似不同的病理如何相关提供了一个框架，并为发现小脑可能调节额叶皮质功能的神经化学、电生理和解剖学机制提供了一个独特的机会，特别是关注多巴胺和浦肯野细胞的数量。随着这个神经回路中的功能相互作用和适应的细节变得已知，这些神经底物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.