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Although the monogenic basis of HD is well defined\n                    <jats:sup>2<\/jats:sup>\n                    , the complex downstream effects that underlie behavioural symptoms are poorly understood. These effects include cortical dysfunction\n                    <jats:sup>3,4<\/jats:sup>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10671-9","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:27:21Z","timestamp":1782919641000},"page":"1262-1270","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Restoring cortical disinhibition improves Huntington\u2019s disease phenotypes"],"prefix":"10.1038","volume":"655","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8124-3295","authenticated-orcid":false,"given":"Sonja","family":"Blumenstock","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Arakelyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6862-9353","authenticated-orcid":false,"given":"Nicholas","family":"del Grosso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2919-6881","authenticated-orcid":false,"given":"Yufeng","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enida","family":"Gjoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3109-0163","authenticated-orcid":false,"given":"R\u00fcdiger","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-8485","authenticated-orcid":false,"given":"Irina","family":"Dudanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9609-4600","authenticated-orcid":false,"given":"Takaki","family":"Komiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"10671_CR1","doi-asserted-by":"publisher","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","volume":"1","author":"GP Bates","year":"2015","unstructured":"Bates, G. 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