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

Abstract

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other 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 within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [¹⁸F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [¹⁸F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).

Fig. 1. Validation of transductions.

A, B Retrograde transduction of Cre-positive tyrosine hydroxylase (TH) expressing neurons in the dorsomedial striatum. C Immunohistochemical staining of mCherry in dorsomedial striatum and in substantia nigra. D Viral vectors used in the vehicle (mDS-mCherry) and chemogenetic (mDS-DREADD) transduction groups. E, G, I Fluorescent microscopy of mCherry (viral transducted) and TH-positive (dopamine) cells in the mesencephalon. F, H, J Magnifications of individual transducted cells (two examples labeled with white arrows) in the SN.

Fig. 2. Open field behavior.

A, B Velocity over time in the open field. C Total distance traveled over the whole-time course. D Tracking of the median mDS-DREADD rat before and after CNO. E–H Total time spent moving, in the center of the open field, rearing or grooming. I–L Frequency of movement initiations, entries into the center square, rearings or grooming bouts. (♂ = ▴) (♀ = ▾).

Fig. 3. Acoustic startle response and prepulse inhibition.

A–C Startle response to various volumes of pulses. D, E Startle response and effect of mDS-DREADD activation at high volume (110 dB) pulses and low volume (81 dB) prepulses. F, G PPI as a result of prepulse intensities, negative PPI values are not shown in F and G to simplify the graph but were included in the statistical analysis. H, I All PPI values at the lowest prepulse intensity (69 dB) pre and post CNO treatment to activate the nigro-striatal dopaminergic pathway. (♂ = ▴) (♀ = ▾).

Fig. 4. [¹⁸F]FDG images and correlation analysis.

A [¹⁸F]FDG uptake in mDS-DREADD animal at baseline and after chemogenetic (CNO) stimulation (rainbow color), lower metabolic activity (blue color), higher metabolic activity (red color). B Regional standard uptake values at all conditions and C significant changes and individual animals in mDS, mPFC, and OFC. (♂ = ▴) (♀ = ▾). D Fisher-Z correlations in mDS-DREADD animals at baselines. E Similar correlations in mDS-DREADD animals after chemogenetic stimulations. F ΔZ values for each region, showing the total difference between correlations. Nucleus acumbens (NAc), medial dorsal striatum (mDS), lateral dorsal striatum (lDS), anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), thalamus (Thal), the midbrain including ventral tegmental area and substantia nigra (MB), hypthalamus (Hyp) and cerebellum (Cer).

Fig. 5. MR spectroscopy of neurochemicals in mDS-DREADD and mDS-mCherry animals.

A Voxel placement in mPFC (blue voxel) and DS (green voxel). B, C Sample spectra from the mPFC and DS. D, F Neurochemical concentrations in the mPFC in all conditions, E, G significant changes in glutamate on the individual level. (♂ = ▴) (♀ = ▾). Medial prefrontal cortex (mPFC), dorsal striatum (DS), creatine (Cr), phosphocreatine (PCr), glutamine (Gln), glutamate (Glu), N-acetyl-aspartate (NAA) and N-acetyl-aspartatylglutamate (NAAG).