Dataset Information

Single-cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson's disease.

ABSTRACT: Exposure to pesticides in humans increases the risk of Parkinson's disease (PD), but the mechanisms remain poorly understood. To elucidate these pathways, we dosed C57BL/6J mice with a combination of the pesticides maneb and paraquat. Behavioral analysis revealed motor deficits consistent with PD. Single-cell RNA sequencing of substantia nigra pars compacta revealed both cell-type-specific genes and genes expressed differentially between pesticide and control, including Fam241b, Emx2os, Bivm, Gm1439, Prdm15, and Rai2. Neurons had the largest number of significant differentially expressed genes, but comparable numbers were found in astrocytes and less so in oligodendrocytes. In addition, network analysis revealed enrichment in functions related to the extracellular matrix. These findings emphasize the importance of support cells in pesticide-induced PD and refocus our attention away from neurons as the sole agent of this disorder.

SUBMITTER: Khan AH

PROVIDER: S-EPMC9438968 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Single-cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson's disease.

Khan Arshad H AH Lee Lydia K LK Smith Desmond J DJ

Translational neuroscience 20220101 1

Exposure to pesticides in humans increases the risk of Parkinson's disease (PD), but the mechanisms remain poorly understood. To elucidate these pathways, we dosed C57BL/6J mice with a combination of the pesticides maneb and paraquat. Behavioral analysis revealed motor deficits consistent with PD. Single-cell RNA sequencing of substantia nigra pars compacta revealed both cell-type-specific genes and genes expressed differentially between pesticide and control, including <i>Fam241b</i>, <i>Emx2os ...[more]

PMID: 36117858

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Project description:The substantia nigra pars compacta (SNc), one of the main dopaminergic nuclei of the brain, exerts a regulatory function on the basal ganglia circuitry via the nigro-striatal pathway but its possible dopaminergic innervation of the thalamus has been only investigated in non-human primates. The impossibility of tract-tracing studies in humans has boosted advanced MRI techniques and multi-shell high-angular resolution diffusion MRI (MS-HARDI) has promised to shed more light on the structural connectivity of subcortical structures. Here, we estimated the possible dopaminergic innervation of the human thalamus via an MS-HARDI tractography of the SNc in healthy human young adults. Two MRI data sets were serially acquired using MS-HARDI schemes from ADNI and HCP neuroimaging initiatives in a group of 10 healthy human subjects (5 males, age range: 25-30 years). High resolution 3D-T1 images were independently acquired to individually segment the thalamus and the SNc. Starting from whole-brain probabilistic tractography, all streamlines through the SNc reaching the thalamus were counted, separately for each hemisphere, after excluding streamlines through the substantia nigra pars reticulata and all those reaching the basal ganglia, the cerebellum and the cortex. We found a reproducible structural connectivity between the SNc and the thalamus, with an average of ~12% of the total number of streamlines encompassing the SNc and terminating in the thalamus, with no other major subcortical or cortical structures involved. The first principal component map of dopamine receptor density from a normative PET image data set suggested similar dopamine levels across SNc and thalamus. This is the first quantitative report from in-vivo measurements in humans supporting the presence of a direct nigro-thalamic dopaminergic projection. While histological validation and concurrent PET-MRI remains needed for ultimate proofing of existence, given the potential role of this pathway, the possibility to achieve a good reproducibility of these measurements in humans might enable the monitoring of dopaminergic-related disorders, towards targeted personalized therapies.

Dataset Information

Single-cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson's disease.

Publications

Single-cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson's disease.

Similar Datasets

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