Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons, but unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning, tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.

中文翻译：

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与种子α-突触核蛋白包涵体的小鼠杏仁核和皮质功能障碍有关的行为缺陷。

帕金森氏病（PD）由运动症状定义，例如静息震颤，运动迟缓，姿势不稳和僵硬。除了定义PD的经典运动缺陷外，多达80％的患者还会经历认知变化和精神疾病，称为PD痴呆（PDD）。病理学上，PD的特征是黑质致密部（SNpc）中的多巴胺能神经元丢失以及称为路易小体和路易神经突的细胞内包裹体，其中大部分由α-突触核蛋白组成。由于纹状体多巴胺的丢失对经典运动表型的影响，PD的许多研究都集中在α-突触核蛋白聚集体在SNpc多巴胺神经元变性中的作用。但是，在其他大脑区域（包括大脑皮层和边缘大脑区域，如杏仁核，杏仁核，这可能有助于非运动型。对于这些大脑区域或多巴胺神经元以外的神经元亚型中的α-突触核蛋白包涵体的后果知之甚少。该项目扩大了关于α-突触核蛋白内含物如何破坏行为，特别是突触核蛋白病的非运动性症状的知识。我们表明，向纹状体的双侧原纤维注射导致皮质和杏仁核中健壮的双侧α-突触核蛋白包涵体形成。杏仁核和前额叶皮层中的夹杂物主要定位于兴奋性神经元，但无偏见的立体显示杏仁核或皮层中神经元没有明显损失。注射原纤维的小鼠在社交支配行为任务和恐惧调节方面表现出缺陷，这些任务与额叶前额叶皮层和杏仁核功能相关。一起，