Abstract
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.
Highlights
Disturbances in the dopaminergic system are crucially involved in many neuropsychiatric disorders including schizophrenia, attention-deficit-hyperactivity disorder (ADHD), addiction, bipolar disorder, and obsessive-compulsive disorder (OCD), underlying motor impairments, hallucinations, and cognitive and emotional deficits [1, 2]
We have focused our functional analysis on the motor, limbic and associative loops with striatum at their core, as (a) dopaminergic alterations within these circuits lead to disturbances in motor, affective and cognitive domains, characteristic for ADHD, OCD and schizophrenia; (b) striatum exhibited the most robust structural changes in the first part of our analysis
Deformation-based morphometry (DBM) analysis reveals broad volume changes encompassing motor, associative and limbic loops Finding a significant reduction in total brain volume (TBV) of dopamine transporter (DAT)-KO rats compared to DAT-HET (p < 0.001) and WT rats (p < 0.05) (Fig. S6), we included it as a covariate to avoid confounding effects
Summary
Disturbances in the dopaminergic system are crucially involved in many neuropsychiatric disorders including schizophrenia, attention-deficit-hyperactivity disorder (ADHD), addiction, bipolar disorder, and obsessive-compulsive disorder (OCD), underlying motor impairments, hallucinations, and cognitive and emotional deficits [1, 2]. These disorders are often comorbid and present overlapping symptoms with common etiology [3, 4]. The investigation of how specific disturbances in dopaminergic signaling affect neural circuits on the systems-level can reveal common transdiagnostic dopamine-related pathomechanisms, contributing to biologically-based understanding according to the Research Domain Criteria framework [5].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
