纹状体星形胶质细胞的化学发生控制改善小鼠帕金森运动缺陷。

IF 5.1 2区 医学 Q1 NEUROSCIENCES
Glia Pub Date : 2025-02-04 DOI:10.1002/glia.24679
Wesley R. Evans, Sindhuja S. Baskar, Angelica Vellore, Ana Raquel Castro E. Costa, Cynthia Jacob, Sanya Ravoori, Abimbola Arigbe, Rafiq Huda
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引用次数: 0

摘要

帕金森病(PD)的特征是多巴胺能黑质纹状体输入的退化,导致纹状体网络功能障碍并导致明显的运动缺陷。最近的证据强调星形胶质细胞是纹状体神经调节的潜在局部来源。有大量证据表明,在运动和运动过程中,去甲肾上腺素介导的皮质星形胶质细胞活动的募集。然而,目前尚不清楚纹状体中的星形胶质细胞如何在运动过程中做出反应,纹状体是一个缺乏去甲肾上腺素神经调节输入的区域。此外,多巴胺丢失如何影响纹状体星形胶质细胞活性以及星形胶质细胞活性是否调节PD的行为缺陷仍不清楚。我们通过使用体内纤维光度法和化学遗传学进行星形胶质细胞特异性钙记录和操作来解决这些问题。我们发现运动引起星形胶质细胞钙活性的时间尺度比神经元要慢。急性药物阻断多巴胺受体只能适度降低运动相关星形胶质细胞活性。然而,单侧多巴胺消耗显著减弱星形胶质细胞钙反应。化学发生刺激gi偶联受体部分改善了多巴胺损伤小鼠的功能性星形胶质细胞缺陷。同时,化学发生操作恢复了不对称运动缺陷,并适度改善了开放领域的探索行为。总之,我们的研究结果确立了功能性纹状体星形细胞信号在PD运动功能调节中的新作用,并强调了PD潜在治疗的非神经元靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Chemogenetic Control of Striatal Astrocytes Improves Parkinsonian Motor Deficits in Mice

Chemogenetic Control of Striatal Astrocytes Improves Parkinsonian Motor Deficits in Mice

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source for striatal neuromodulation. There is substantial evidence for norepinephrine-mediated recruitment of cortical astrocyte activity during movement and locomotion. However, it is unclear how astrocytes in the striatum, a region devoid of norepinephrine neuromodulatory inputs, respond during locomotion. Moreover, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte-specific calcium recordings and manipulations using in vivo fiber photometry and chemogenetics. We find that locomotion elicits astrocyte calcium activity over a slower timescale than neurons. Acute pharmacological blockade of dopamine receptors only moderately reduced locomotion-related astrocyte activity. Yet, unilateral dopamine depletion significantly attenuated astrocyte calcium responses. Chemogenetic stimulation of Gi-coupled receptors partially improved this functional astrocyte deficit in dopamine-lesioned mice. In parallel, chemogenetic manipulation restored asymmetrical motor deficits and moderately improved open-field exploratory behavior. Together, our results establish a novel role for functional striatal astrocyte signaling in modulating motor function in PD and highlight non-neuronal targets for potential PD therapeutics.

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来源期刊
Glia
Glia 医学-神经科学
CiteScore
13.10
自引率
4.80%
发文量
162
审稿时长
3-8 weeks
期刊介绍: GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.
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