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Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, <jats:italic>N<\/jats:italic>\u2009=\u200914), heterozygous knockout (<jats:italic>N<\/jats:italic>\u2009=\u20098) and wild-type male rats (<jats:italic>N<\/jats:italic>\u2009=\u200914). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.<\/jats:p>","DOI":"10.1038\/s41380-022-01471-4","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T13:33:32Z","timestamp":1646400812000},"page":"2329-2339","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9508-3942","authenticated-orcid":false,"given":"Jonathan R.","family":"Reinwald","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7654-0570","authenticated-orcid":false,"given":"Natalia","family":"Gass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne S.","family":"Mallien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Sartorius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-4452","authenticated-orcid":false,"given":"Robert","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Sack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Falfan-Melgoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7510-2325","authenticated-orcid":false,"given":"Christian","family":"Clemm von Hohenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiana","family":"Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascha","family":"Pfeiffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonieke","family":"Middelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meyer-Lindenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7621-1010","authenticated-orcid":false,"given":"Judith R.","family":"Homberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Weber-Fahr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"1471_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s10571-018-0632-3","volume":"39","author":"MO Klein","year":"2019","unstructured":"Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG. 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AM-L has received consultant fees from: Agence Nationale de la Recherche, Brain Mind Institute, Brainsway, CISSN (Catania International Summer School of Neuroscience), Daimler und Benz Stiftung, Fondation FondaMental, Hector Stiftung II, Janssen-Cilag GmbH, Lundbeck A\/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, MedinCell, Sage Therapeutics, Techspert.io, The LOOP Z\u00fcrich, University Medical Center Utrecht, von Behring R\u00f6ntgen Stiftung. AM-L has received speaker fees from: \u00c4rztekammer Nordrhein, BAG Psychiatrie Oberbayern, Biotest AG, Forum Werkstatt Karlsruhe, International Society of Psychiatric Genetics, Brentwood, Klinik f\u00fcr Psychiatrie und Psychotherapie Ingolstadt, Lundbeck SAS France, med Update GmbH, Merz-Stiftung, Siemens Healthineers, Society of Biological Psychiatry. AM-L has received editorial fees from: American Association for the Advancement of Science, Elsevier, Thieme Verlag.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}