Dorsal striatal dopamine induces fronto-cortical hypoactivity and implies reduced anxiety and compulsive behaviors in rats

Abstract

Nigro-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.

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

“…Anaesthesia was induced using 3% isoflurane in oxygen. All rats were placed in a 2 × 2 custom made rat holder (illustration in Figure 1 ), enabling simultaneous scanning of four rats ( Keller et al, 2017 ; Shalgunov et al, 2020 ; Casado-Sainz et al, 2021 ). While in the custom-made rat holder, the rats were kept under anaesthesia with a constant flow of isoflurane (∼2% isoflurane in oxygen).…”

“…The regions (depicted in Figure 3 and Supplementary Figure 5 ) included in this study were: anterior cingulate cortex, medial prefrontal cortex, motor cortex, nucleus accumbens, orbitofrontal cortex, striatum, thalamus, and ventral midbrain (a region covering both the ventral tegmental area and substantia nigra). The dorsomedial striatum and dorsolateral striatum were manually delineated and used in the study ( Shalgunov et al, 2020 ; Casado-Sainz et al, 2021 ). All images and co-registration were visually checked for accuracy following spatial transformation.…”

Synaptic density and neuronal metabolic function measured by PET in the unilateral 6-OHDA rat model of Parkinson’s disease

“…The regions (depicted in Figure 3 and Supplementary Figure 1) included in this study were: anterior cingulate cortex, medial prefrontal cortex, motor cortex, nucleus accumbens, orbitofrontal cortex, striatum, thalamus, and ventral midbrain (a region covering both the ventral tegmental area and substantia nigra). The dorsomedial striatum and dorsolateral striatum were manually delineated and used in the study (Shalgunov et al, 2020; Casado-Sainz et al, 2021). All images and co-registration were visually checked for accuracy following spatial transformation.…”