Cerebellar Modulation of Frontal Cortical Function

额叶皮质功能的小脑调节

• 批准号: 8418762
• 负责人: Charles Blaha
• 金额: $ 28.7万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418762
• 关键词: Accounting; Autistic Disorder; Behavior; Behavioral; Brain; Cell Count; Cells; Cerebellar Nuclei; Cerebellar cortex structure; Cerebellum; Chimera organism; Cognitive deficits; Communication; Congenital cerebellar hypoplasia; Data; Development; Dopamine; Embryo; Exhibits; Genes; Glutamates; Health; Impaired cognition; Impairment; Individual; Lead; Life; Lurcher Mouse; Mediating; Modeling; Motor Ataxias; Mus; Mutation; Neural Pathways; Neurons; Nuclear; Pathology; Pathway interactions; Pattern; Performance; Physiological; Prefrontal Cortex; Process; Purkinje Cells; Reporting; Reversal Learning; Staging; Structure; Syndrome; System; Testing; autism spectrum disorder; base; developmental disease; extracellular; frontal lobe; mutant; neural circuit; neurochemistry; neuromechanism; neuropsychiatry; receptor; relating to nervous system; research study; response; restoration

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.

描述（由申请人提供）：在自闭症谱系中发生的小脑Purkinje细胞的发育丧失与认知缺陷的异质模式有关，而认知缺陷无法通过单一的认知障碍来解释。小脑浦肯野细胞的简单损失不可能直接解决这些无数认知缺陷。相反，自闭症本质上可能是一种断开综合征，至少部分是由于前额叶皮层（PFC）的小脑调节的破坏而导致的。我们有令人兴奋的新数据，表明小脑会调节PFC多巴胺水平。在这里，我们提出了以下脱节假说：小脑病理学导致前额叶皮层（PFC）导致多巴胺能异常，并构成了一些自闭症的核心神经精神症状。在AIM 1中，我们将确定小脑在PFC中调节多巴胺的释放，在PFC中调节多巴胺的释放，其中包括小脑到PFC途径的小脑以及神经化学，电生理学，解剖学，解剖学和行为后果。 AIM 1将比较野生型（对照）和Lurcher小鼠与所有Purkinje细胞的松动，以确定Purkinje细胞完全丢失在小脑PFC通信上的后果。 AIM 2将研究浦肯野细胞部分丧失的行为和生理后果 - 通常在自闭症大脑中发现。使用Purkinje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，解剖学和行为指标如何取决于Purkinje细胞数。鉴于在自闭症谱系障碍中发现的小脑神经元数量的减少，嵌合小鼠的神经化学，电生理学，解剖学和行为分析提供了一个独特的机会，这是对这些综合症的发育和小脑方面进行建模的独特机会。

项目成果

Reorganization of circuits underlying cerebellar modulation of prefrontal cortical dopamine in mouse models of autism spectrum disorder.

• DOI: 10.1007/s12311-013-0462-2
• 发表时间: 2013-08
• 期刊: CEREBELLUM
• 影响因子: 3.5
• 作者: Rogers, Tiffany D.;Dickson, Price E.;McKimm, Eric;Heck, Detlef H.;Goldowitz, Dan;Blaha, Charles D.;Mittleman, Guy
• 通讯作者: Mittleman, Guy

Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss.

• DOI: 10.1016/j.nlm.2010.05.010
• 发表时间: 2010-09
• 期刊: NEUROBIOLOGY OF LEARNING AND MEMORY
• 影响因子: 2.7
• 作者: Dickson, Price E.;Rogers, Tiffany D.;Del Mar, Nobel;Martin, Loren A.;Heck, Detlef;Blaha, Charles D.;Goldowitz, Daniel;Mittleman, Guy
• 通讯作者: Mittleman, Guy

Impaired hypercarbic and hypoxic responses from developmental loss of cerebellar Purkinje neurons: implications for sudden infant death syndrome.

• DOI: 10.1007/s12311-014-0592-1
• 发表时间: 2014-12
• 期刊: CEREBELLUM
• 影响因子: 3.5
• 作者: Calton, M.;Dickson, P.;Harper, R. M.;Goldowitz, D.;Mittleman, G.
• 通讯作者: Mittleman, G.

Repetitive behavior and increased activity in mice with Purkinje cell loss: a model for understanding the role of cerebellar pathology in autism.

• DOI: 10.1111/j.1460-9568.2009.07073.x
• 发表时间: 2010-02
• 期刊: The European journal of neuroscience
• 作者: Martin LA;Goldowitz D;Mittleman G
• 通讯作者: Mittleman G

Glutamate dysfunction associated with developmental cerebellar damage: relevance to autism spectrum disorders.

• DOI: 10.1007/s12311-013-0541-4
• 发表时间: 2014-06
• 期刊: CEREBELLUM
• 影响因子: 3.5
• 作者: McKimm, Eric;Corkill, Beau;Goldowitz, Dan;Albritton, Lorraine M.;Homayouni, Ramin;Blaha, Charles D.;Mittleman, Guy
• 通讯作者: Mittleman, Guy