Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypes associated with obsessive-compulsive disorder

AbstractNigro-striatal dopamine transmission in the rat dorsomedial striatum (DMS) engages the cortico-striato-thalamo-cortical (CSTC) circuit. Modulation of the CSTC circuit can emulate behavioral and functional aspects of neuropsychiatric diseases, including obsessive compulsive disorder (OCD). Classical pharmacological and neurotoxic manipulations of brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations. In this study, we developed a chemogenetic method for selective activation of dopamine neurons innervating the rat DMS, and used this approach to investigate effects of targeted dopamine activation on CSTC circuit function. We monitored behavioral effects on locomotion, self-grooming, and prepulse inhibition of the startle response, which are stereotypic behaviors related to OCD, as well as effects on metabolic functional connectivity measured by [18F]FDG PET, and regional concentrations of neurochemicals (i.e., glutamate, glutamine, N-acetylaspartate and N-acetylaspartateglutamate) measured by MR spectroscopy. We found that chemogenetic induced nigro-striatal dopamine transmission lowers some of the stereotypic behaviors that are considered hallmarks of OCD. It also disrupts functional connectivity between cortical areas and striatum, and increased total glutamate and N-acetylaspatateglutamate in cortical regions. The results thus establishes the importance of nigro-striatal dopamine transmission in modulation of CSTC function and emphasize DMS dopamine as a possible target for treatment of related neuropsychiatric disorders.One Sentence SummaryChemogenetic nigro-striatal dopamine activation modulates functional connectivity and behaviors related to cortico-striato-thalamo-cortical circuit – perspectives for the treatment of obsessive-compulsive disorder.

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Functional Connectivity of the Striatum as a Neural Correlate of Symptom Severity in Patient with Obsessive-Compulsive Disorder

Psychiatry Investigation ◽

10.30773/pi.2019.0206 ◽

2020 ◽

Vol 17 (2) ◽

pp. 87-95 ◽

Cited By ~ 1

Author(s):

Junha Park ◽

Taekwan Kim ◽

Minah Kim ◽

Tae Young Lee ◽

Jun Soo Kwon

Keyword(s):

Functional Connectivity ◽

Obsessive Compulsive Disorder ◽

Symptom Severity ◽

Rating Scale ◽

Neural Correlates ◽

Current Evidence ◽

Obsessive Compulsive ◽

Compulsive Disorder ◽

Cortical Regions ◽

Hamilton Rating Scale

Objective It is well established that the cortico-striato-thalamo-cortical (CSTC) circuit is implicated in the pathophysiology of obsessive- compulsive disorder (OCD). However, reports on corticostriatal functional connectivity (FC) in OCD have been inconsistent due to the structural and functional heterogeneity of the striatum. Therefore, in the present study, we investigated corticostriatal FC using a fine 12-seed striatal parcellation to overcome this heterogeneity and discover the neural correlates of symptoms in OCD patients.Methods We recruited 23 OCD patients and 23 healthy controls (HCs). Whole-brain FC based on striatal seeds was examined using resting-state functional magnetic resonance imaging data and compared across OCD patients and HCs. We conducted correlation analysis between FCs of striatal subregions with significant group differences and symptom severity scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Rating Scale for Depression, and Hamilton Rating Scale for Anxiety (HAM-A).Results Compared to HCs, patients demonstrated increased FC of the dorsal caudal putamen and ventral rostral putamen (VRP) with several cortical regions, such as the intracalcarine cortex, inferior frontal gyrus, supramarginal/angular gyrus (SMG/AG), and postcentral gyrus (PCG). Furthermore, FC between the VRP and SMG/AG and between the VRP and PCG was negatively correlated with scores on the Y-BOCS compulsive subscale and the HAM-A, respectively.Conclusion These findings suggest that striatal subregions have strengthened FC with extensive cortical regions, which may reflect neural correlates of compulsive and anxious symptoms in OCD patients. These results contribute to an improved understanding of OCD pathophysiology by complementing the current evidence regarding striatal FC.

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