Newly generated striatal neurons rescue motor circuitry in a Huntington's disease mouse model.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-22 Epub Date: 2025-04-07 DOI:10.1016/j.celrep.2025.115440

Jose C Cano, Cathryn Mangiamele, Maiken Nedergaard, Abdellatif Benraiss, Steven A Goldman

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引用次数: 0

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by the selective loss of neostriatal medium spiny neurons (MSNs). We previously found that intraventricular delivery of viral vectors expressing brain-derived neurotrophic factor (BDNF) and Noggin induced heterotopic recruitment of new MSNs to the adult neostriatum and slowed disease progression in the R6/2 mouse model of HD. Nonetheless, the extent to which newly generated neurons integrate into adult striatal circuits has remained unclear. Here, using wild-type (WT) and R6/2 mice, we follow the fate of genetically tagged new neurons recruited to the striatum after intraventricular infusion of BDNF and Noggin. Using rabies tract tracing, optogenetics, and calcium imaging, we find that new neurons functionally assimilate into the cortico-striato-pallidal motor circuitry, and chemogenetic stimulation of these new neurons confirms their contribution to motor behavior. Together, these data indicate that induced neurogenesis may restore multi-synaptic circuits in the adult brain, offering a regenerative strategy for the treatment of HD.

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新生成的纹状体神经元在亨廷顿氏病小鼠模型中拯救运动回路。

亨廷顿氏病（HD）是一种致命的神经退行性疾病，其特征是新纹状体中棘神经元（msn）的选择性丧失。我们之前发现，在R6/2 HD小鼠模型中，脑室内递送表达脑源性神经营养因子（BDNF）和Noggin的病毒载体诱导新的msn异位募集到成年新纹状体，并减缓疾病进展。尽管如此，新生成的神经元在多大程度上整合到成年纹状体回路中仍不清楚。在这里，我们使用野生型（WT）和R6/2小鼠，跟踪在脑室内注入BDNF和Noggin后纹状体募集的遗传标记新神经元的命运。通过狂犬病道追踪、光遗传学和钙成像，我们发现新神经元在功能上融入皮质-纹状体-白质运动回路，这些新神经元的化学发生刺激证实了它们对运动行为的贡献。总之，这些数据表明，诱导神经发生可能恢复成人大脑中的多突触回路，为治疗HD提供了一种再生策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.