The Aggregation of α-Synuclein in the Dorsomedial Striatum Significantly Impairs Cognitive Flexibility in Parkinson’s Disease Mice

Author:

Chen Jing1ORCID,Liu Yifang2,Su Mingyu2,Sun Yaoyu2,Liu Chenkai2,Sun Sihan2,Wang Ting3,Tang Chuanxi24ORCID

Affiliation:

1. School of Basic Medical Science, Xuzhou Medical University, Xuzhou 221004, China

2. Department of Neurobiology, Xuzhou Medical University, Xuzhou 221004, China

3. The Second Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, China

4. The Research and Engineering Center of Xuzhou Neurodegenerative Disease Diagnosis and Treatment Biologics, Xuzhou Medical University, Xuzhou 221004, China

Abstract

This study focused on α-synuclein (α-syn) aggregation in the dorsomedial striatum (DMS) so as to investigate its role in the cognitive flexibility of Parkinson’s disease (PD). Here, we investigated the cognitive flexibility by assessing reversal learning abilities in MPTP-induced subacute PD model mice and in C57BL/6J mice with α-syn aggregation in the DMS induced by adenovirus (AAV-SNCA) injection, followed by an analysis of the target protein’s expression and distribution. PD mice exhibited impairments in reversal learning, positively correlated with the expression of phosphorylated α-syn in the DMS. Furthermore, the mice in the AAV-SNCA group exhibited reversal learning deficits and a reduction in acetylcholine levels, accompanied by protein alterations within the DMS. Notably, the administration of a muscarinic receptor 1 (M1R) agonist was able to alleviate the aforementioned phenomenon. These findings suggest that the impaired cognitive flexibility in PD may be attributed to the diminished activation of acetylcholine to M1R caused by α-syn aggregation.

Funder

Jiangsu Province Science Foundation for Youths

Research Foundation for Talented Scholars of Xuzhou Medical University

Postgraduate Research & Practice Innovation Program of Jiangsu Province

Innovation and Entrepreneurship Training Programme for University Students

Publisher

MDPI AG

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