Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits
Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar...
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| Hauptverfasser: | , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
4 March 2022
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| In: |
Molecular psychiatry
Year: 2022, Jahrgang: 27, Heft: 4, Pages: 2329-2339 |
| ISSN: | 1476-5578 |
| DOI: | 10.1038/s41380-022-01471-4 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41380-022-01471-4 Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41380-022-01471-4 
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| Verfasserangaben: | Jonathan R. Reinwald, Natalia Gass, Anne S. Mallien, Alexander Sartorius, Robert Becker, Markus Sack, Claudia Falfan-Melgoza, Christian Clemm von Hohenberg, Damiana Leo, Natascha Pfeiffer, Anthonieke Middelman, Andreas Meyer-Lindenberg, Judith R. Homberg, Wolfgang Weber-Fahr and Peter Gass |
| Zusammenfassung: | Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). 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, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). 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. |
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| Beschreibung: | Gesehen am 25.03.2024 |
| Beschreibung: | Online Resource |
| ISSN: | 1476-5578 |
| DOI: | 10.1038/s41380-022-01471-4 |