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Reinwald, Jonathan Rochus [VerfasserIn]; Gass, Natalia [VerfasserIn]; Mallien, Anne S. [VerfasserIn]; Sartorius, Alexander [VerfasserIn]; Becker, Robert [VerfasserIn]; Sack, Markus [VerfasserIn]; Falfán‐Melgoza, Claudia [VerfasserIn]; Clemm von Hohenberg, Christian [VerfasserIn]; Leo, Damiana [VerfasserIn]; Pfeiffer, Natascha [VerfasserIn]; Middelman, Anthonieke [VerfasserIn]; Meyer-Lindenberg, Andreas [VerfasserIn]; Homberg, Judith R. [VerfasserIn]; Weber-Fahr, Wolfgang [VerfasserIn]; Gass, Peter [VerfasserIn]

Dopamine transporter silencing in the rat : systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

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  • Medientyp: E-Artikel
  • Titel: Dopamine transporter silencing in the rat : systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits
  • Beteiligte: Reinwald, Jonathan Rochus [VerfasserIn]; Gass, Natalia [VerfasserIn]; Mallien, Anne S. [VerfasserIn]; Sartorius, Alexander [VerfasserIn]; Becker, Robert [VerfasserIn]; Sack, Markus [VerfasserIn]; Falfán‐Melgoza, Claudia [VerfasserIn]; Clemm von Hohenberg, Christian [VerfasserIn]; Leo, Damiana [VerfasserIn]; Pfeiffer, Natascha [VerfasserIn]; Middelman, Anthonieke [VerfasserIn]; Meyer-Lindenberg, Andreas [VerfasserIn]; Homberg, Judith R. [VerfasserIn]; Weber-Fahr, Wolfgang [VerfasserIn]; Gass, Peter [VerfasserIn]
  • Erschienen: 4 March 2022
  • Erschienen in: Molecular psychiatry ; 27(2022), 4, Seite 2329-2339
  • Sprache: Englisch
  • DOI: 10.1038/s41380-022-01471-4
  • ISSN: 1476-5578
  • Identifikator:
  • Schlagwörter: ADHD ; Bipolar disorder ; Genetics ; Neuroscience ; Schizophrenia
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: 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.
  • Zugangsstatus: Freier Zugang