Parkinson’s disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [11C]UCB-J and [18F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [11C]UCB-J binding and [18F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuit’s cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [11C]UCB-J and [18F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

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The combination of neuroimaging and targeted neuromodulation is a crucial tool to gain a deeper understanding of neural networks at a circuit level. Infrared neurostimulation (INS) is a promising optical modality that allows to evoke neuronal activity with high spatial resolution without need for the introduction of exogenous substances in the brain. Here, we report the use of whole-brain functional [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging during INS in the dorsal striatum, performed using a multifunctional soft neural probe. We demonstrate the possibility to identify multi-circuit connection patterns in both cortical and subcortical brain regions within a single scan. By using a bolus plus infusion FDG-PET scanning protocol, we were able to observe the metabolic rate evolution in these regions during the experiments and correlate its variation with the onset of the INS stimulus. Due to the focality of INS and the large amount of viable molecular targets for PET, this novel approach to simultaneous imaging and stimulation is highly versatile. This pilot study can pave the way to further understand the brain connectivity on a global scale.

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.