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异质性的认知缺陷模式有关，这种模式不能用单一的认知障碍来解释。小脑浦肯野细胞的简单损失不太可能直接解释这些无数的认知缺陷。相反，从本质上讲，自闭症很可能是一种断开综合症，至少部分原因是小脑前额皮质（PFC）调节功能的中断。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，我们建议研究断开假说，即小脑病理导致前额叶皮层（PFC）多巴胺能异常，并成为自闭症的一些核心神经精神症状的基础。在目的1中，我们将确定小脑调节PFC中多巴胺释放和组成小脑到PFC通路的亚核中谷氨酸释放的途径，以及这两个结构之间断开的神经化学、电生理、解剖学和行为后果。目的1将比较野生型（对照）和丢失所有浦肯野细胞的Lurcher小鼠，以确定浦肯野细胞完全丢失对小脑- pfc通信的影响。目标2将研究部分浦肯野细胞丢失的行为和生理后果——这通常在自闭症大脑中发现。使用浦肯野细胞数量不同发育损失的Lurcher-wildtype嵌合体，我们将确定PFC功能的神经化学、电生理、解剖和行为指标如何依赖于浦肯野细胞数量。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记录，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。小脑和额叶皮质病变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。这一建议提出了一个框架来理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，发现神经化学，电生理和解剖机制，小脑可能调节额叶皮质功能，特别关注多巴胺和浦肯野细胞数量。随着神经回路中功能相互作用和适应的细节被了解，这些神经基质和相关受体机制应该成为治疗自闭症相关认知缺陷的新候选。

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.