加州大学Takaki Komiyama小组的一项最新研究发现了恢复皮层去抑制可改善亨廷顿氏病的表型。2026年7月1日出版的《自然》杂志发表了这项成果。

本研究采用纵向体内双光子钙成像技术检测转基因R6/2 HD小鼠模型运动皮层中三种皮质抑制性神经元（IN）亚型和兴奋性皮质纹状体（CStr）投射神经元在疾病进展过程中的活性。研究组发现R6/2小鼠的运动缺陷伴随着运动相关活动的神经元亚型特异性异常。这包括血管活性肠肽(VIP)-INs和CStr神经元的明显活性降低，这在敲入zQ175DN HD小鼠模型中也观察到。光遗传学激活R6/2小鼠VIP-INs恢复了VIP-INs及其下游CStr神经元的健康活性水平，改善了R6/2小鼠的运动缺陷；行为改善在刺激后持续数天。他们的发现强调皮质蛋白是HD的潜在治疗靶点。

据了解，亨廷顿舞蹈症（HD）是一种毁灭性的运动障碍，目前无法治愈。虽然HD的单基因基础已经明确，但行为症状背后复杂的下游效应却知之甚少。这些影响包括皮质功能障碍，但特定皮质神经元亚型在HD症状中的作用在很大程度上仍未被探索。

附：英文原文

Title: Restoring cortical disinhibition improves Huntington’s disease phenotypes

Author: Blumenstock, Sonja, Arakelyan, David, del Grosso, Nicholas, Schneider, Sonja, Shao, Yufeng, Gjoni, Enida, Klein, Rdiger, Dudanova, Irina, Komiyama, Takaki

Issue&Volume: 2026-07-01

Abstract: Huntington’s disease (HD) is a devastating movement disorder without a cure at present1. Although the monogenic basis of HD is well defined2, the complex downstream effects that underlie behavioural symptoms are poorly understood. These effects include cortical dysfunction3,4, yet the roles of specific cortical neuronal subtypes in HD symptoms remain largely unexplored. Here we used longitudinal in vivo two-photon calcium imaging to examine the activity of three cortical inhibitory neuron (IN) subtypes and excitatory corticostriatal (CStr) projection neurons in the motor cortex of the transgenic R6/2 HD mouse model throughout disease progression. We found that motor deficits in R6/2 mice were accompanied by neuron subtype-specific abnormalities in movement-related activity. This included marked hypoactivity of vasoactive intestinal peptide (VIP)-INs and CStr neurons, which was also observed in the knock-in zQ175DN HD mouse model. Optogenetic activation of VIP-INs in R6/2 mice restored healthy levels of activity in VIP-INs and their downstream CStr neurons and ameliorated motor deficits in R6/2 mice; behavioural improvements persisted for days after stimulation. Our findings highlight cortical INs as a potential therapeutic target for HD.

DOI: 10.1038/s41586-026-10671-9

Source: https://www.nature.com/articles/s41586-026-10671-9

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html