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Pourian \u201813 Fund","award":["16KK0182"],"award-info":[{"award-number":["16KK0182"]}]},{"DOI":"10.13039\/501100001691","name":"Robert Buxton, JSPS KAKENHI","doi-asserted-by":"publisher","award":["A-5552"],"award-info":[{"award-number":["A-5552"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Robert Buxton, JSPS KAKENHI","doi-asserted-by":"publisher","award":["R01 MH060379"],"award-info":[{"award-number":["R01 MH060379"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Robert Buxton, JSPS KAKENHI","doi-asserted-by":"publisher","award":["17K10899"],"award-info":[{"award-number":["17K10899"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Robert Buxton, JSPS KAKENHI","doi-asserted-by":"publisher","award":["16KK0182"],"award-info":[{"award-number":["16KK0182"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beauty Life Corporation","award":["A-5552"],"award-info":[{"award-number":["A-5552"]}]},{"name":"Beauty Life Corporation","award":["R01 MH060379"],"award-info":[{"award-number":["R01 MH060379"]}]},{"name":"Beauty Life Corporation","award":["17K10899"],"award-info":[{"award-number":["17K10899"]}]},{"name":"Beauty Life Corporation","award":["16KK0182"],"award-info":[{"award-number":["16KK0182"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pathogenesis and pathophysiology of Huntington\u2019s disease (HD) are still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. Clinical positron emission tomography studies suggest that phosphodiesterase 10A (PDE10A) declines earlier than dopamine D1 and D2 receptors in HD, indicating that it might serve as a key molecular marker in understanding disease mechanisms. In movement disorders, mutations in the genes encoding PDE10A and G-protein \u03b1 subunit (G\u03b1olf), both critical cAMP regulators in striatal spiny projection neurons, have been linked to chorea and dystonia. These observations highlight the potential importance of striatal cyclic AMP (cAMP) signaling in these disorders, but how such dysfunction could come is unknown. Here, we suggest that a key to understanding signaling dysfunction might be to evaluate these messenger systems in light of the circuit-level compartmental organization of the caudoputamen, in which there is particular vulnerability of the striosome compartment in HD. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of Q175 knock-in (Q175KI) HD mice from 3\u201312 months of age. We demonstrate that the expression of multiple molecules, including G\u03b1olf, PDE10A, dopamine D1 and D2 receptors, and adenosine A2A receptors, is significantly reduced in the striosomes of Q175KI mice as compared to wildtype controls, across 3, 6, and 12 months of age. By contrast, mu-opioid receptor (MOR1) expression is uniquely upregulated, suggesting a compartment-specific and age-dependent shift in molecular profiles in the Q175KI HD mouse model caudoputamen. These differential changes may serve as a useful platform to determine factors underlying the greater vulnerability of striatal projection neurons in the striosomes than in the matrix in HD.<\/jats:p>","DOI":"10.3390\/ijms26178573","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:18:57Z","timestamp":1756977537000},"page":"8573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular Imbalances Between Striosome and Matrix Compartments Characterize the Pathogenesis and Pathophysiology of Huntington\u2019s Disease Model Mouse"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4919-6441","authenticated-orcid":false,"given":"Ryoma","family":"Morigaki","sequence":"first","affiliation":[{"name":"McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Advanced Brain Research, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan"},{"name":"Department of Neurosurgery, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan"},{"name":"Parkinson\u2019s Disease and Dystonia Research Center, Tokushima University Hospital, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3961-0095","authenticated-orcid":false,"given":"Tomoko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5082-3759","authenticated-orcid":false,"given":"Joji","family":"Fujikawa","sequence":"additional","affiliation":[{"name":"Department of Advanced Brain Research, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill R.","family":"Crittenden","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4326-7720","authenticated-orcid":false,"given":"Ann M.","family":"Graybiel","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"},{"name":"Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1126\/science.2931802","article-title":"Selective Sparing of a Class of Striatal Neurons in Huntington\u2019s Disease","volume":"230","author":"Ferrante","year":"1985","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/0006-8993(87)90694-9","article-title":"Sparing of Acetylcholinesterase-Containing Striatal Neurons in Huntington\u2019s Disease","volume":"411","author":"Ferrante","year":"1987","journal-title":"Brain Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5733","DOI":"10.1073\/pnas.85.15.5733","article-title":"Differential Loss of Striatal Projection Neurons in Huntington Disease","volume":"85","author":"Reiner","year":"1988","journal-title":"Proc. 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