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Corticostriatal Projections Relying on GABA Levels Mediate Exercise-Induced Functional Recovery in Cerebral Ischemic Mice

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Abstract

Stroke is a neurological disorder characterized by high disability and death worldwide. The occlusion of the middle cerebral artery (MCAO) supplying the cortical motor regions and its projection pathway regions can either kill the cortical neurons or block their projections to the spinal cord and subcortical structure. The cerebral cortex is the primary striatal afferent, and the medium spiny neurons of the striatum have been identified as the major output neurons projecting to the substantia nigra and pallidum. Thus, disconnection of the corticostriatal circuit often occurs in the model of MCAO. In this study, we hypothesize that striatal network dysfunction in cerebral ischemic mice ultimately modulates the activity of striatal projections from cortical neurons to improve dysfunction during exercise training. In this study, we observed that the corticostriatal circuit originating from glutamatergic neurons could partially medicate the improvement of motor and anxiety-like behavior in mice with exercise. Furthermore, exercising or activating a single optogenetic corticostriatal circuit can increase the striatal gamma-aminobutyric acid (GABA) level. Using the GABA-A receptor antagonist, bicuculline, we further identified that the striatal glutamatergic projection from the cortical neurons relies on the GABAergic synapse’s activity to modulate exercise-induced functional recovery. Overall, those results reveal that the dorsal striatum-projecting subpopulation of cortical glutamatergic neurons can influence GABA levels in the striatum, playing a critical role in modulating exercise-induced improvement of motor and anxiety-like behavior.

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Data Availability

All data in the current study are available from the corresponding authors at the reasonable request.

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Funding

This study was funded by the National Natural Science Foundation of China (grant number 81871841).

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    Authors and Affiliations

    1. Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing’an District, Shanghai, 200040, People’s Republic of China

      Ying Xing, Anjing Zhang, Congqin Li, Lu Luo & Yulong Bai

    2. Department of Neurological Rehabilitation Medicine, The First Rehabilitation Hospital of Shanghai, Shanghai, 200093, People’s Republic of China

      Anjing Zhang

    3. State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, Brain Science Collaborative Innovation Center, School of Basic Medical Sciences, Institutes of Brain Science, Fudan Institutes of Integrative Medicine, Fudan University, No. 130 Dong ’An Road, Xuhui District, Shanghai, 200032, People’s Republic of China

      Jing Han, Jun wang & Zhanzhuang Tian

    4. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China

      Xuechun Chang

    5. National Center for Neurological Disorders, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jing’an District, Shanghai, 200040, People’s Republic of China

      Yulong Bai

    6. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Jing’an District, No. 12 Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of China

      Yulong Bai

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    Contributions

    Study design and conception: Ying Xing, Zhanzhuang Tian, Yulong Bai; major experimental implementation: Ying Xing, Anjing Zhang; behavioral tests and data analysis: Congqin Li, Jing Han, Xue Chun Chang; manuscript writing: Ying Xing, Jun Wang, Lu Luo; manuscript revision: Ying Xing, Anjing Zhang. All authors approved the final manuscript before submission for publication.

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    Correspondence to Zhanzhuang Tian or Yulong Bai.

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    Ying Xing and Anjing Zhang are co-first athors and contributed equally to this work.

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    Xing, Y., Zhang, A., Li, C. et al. Corticostriatal Projections Relying on GABA Levels Mediate Exercise-Induced Functional Recovery in Cerebral Ischemic Mice. Mol Neurobiol 60, 1836–1853 (2023). https://doi.org/10.1007/s12035-022-03181-y

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