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Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson's disease.

ABSTRACT: In Parkinson's disease (PD), neurodegeneration of dopaminergic neurons occurs in the midbrain, specifically targeting the substantia nigra (SN), while leaving the ventral tegmental area (VTA) relatively spared in early phases of the disease. Although the SN and VTA are known to be functionally dissociable in healthy adults, it remains unclear how this dissociation is altered in PD. To examine this issue, we performed a whole-brain analysis to compare functional connectivity in PD to healthy adults using resting-state functional magnetic resonance imaging (rs-fMRI) data compiled from three independent datasets. Our analysis showed that across the sample, the SN had greater connectivity with the precuneus, anterior cingulate gyrus, and areas of the occipital cortex, partially replicating our previous work in healthy young adults. Notably, we also found that, in PD, VTA-right cerebellum connectivity was higher than SN-right cerebellum connectivity, whereas the opposite trend occurred in healthy controls. This double dissociation may reflect a compensatory role of the cerebellum in PD and could provide a potential target for future study and treatment.

SUBMITTER: O'Shea IM

PROVIDER: S-EPMC8885704 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson's disease.

O'Shea Ian M IM Popal Haroon S HS Olson Ingrid R IR Murty Vishnu P VP Smith David V DV

Scientific reports 20220228 1

In Parkinson's disease (PD), neurodegeneration of dopaminergic neurons occurs in the midbrain, specifically targeting the substantia nigra (SN), while leaving the ventral tegmental area (VTA) relatively spared in early phases of the disease. Although the SN and VTA are known to be functionally dissociable in healthy adults, it remains unclear how this dissociation is altered in PD. To examine this issue, we performed a whole-brain analysis to compare functional connectivity in PD to healthy adul ...[more]

PMID: 35228561

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Project description:Perturbations in metabolism are a well-documented but complex facet of schizophrenia pathology. Optimal cellular performance requires the proper functioning of the electron transport chain, which is constituted by four enzymes located within the inner membrane of mitochondria. These enzymes create a proton gradient that is used to power the enzyme ATP synthase, producing ATP, which is crucial for the maintenance of cellular functioning. Anomalies in a single enzyme of the electron transport chain are sufficient to cause disruption of cellular metabolism. The last of these complexes is the cytochrome c oxidase (COX) enzyme, which is composed of thirteen different subunits. COX is a major site for oxidative phosphorylation, and anomalies in this enzyme are one of the most frequent causes of mitochondrial pathology. The objective of the present report was to assess if metabolic anomalies linked to COX dysfunction may contribute to substantia nigra/ventral tegmental area (SN/VTA) pathology in schizophrenia. We tested COX activity in postmortem SN/VTA from schizophrenia and non-psychiatric controls. We also tested the protein expression of key subunits for the assembly and activity of the enzyme, and the effect of antipsychotic medication on subunit expression. COX activity was not significantly different between schizophrenia and non-psychiatric controls. However, we found significant decreases in the expression of subunits II and IV-I of COX in schizophrenia. Interestingly, these decreases were observed in samples containing the entire rostro-caudal extent of the SN/VTA, while no significant differences were observed for samples containing only mid-caudal regions of the SN/VTA. Finally, rats chronically treated with antipsychotic drugs did not show significant changes in COX subunit expression. These findings suggest that COX subunit expression may be compromised in specific sub-regions of the SN/VTA (i.e. rostral regions), which may lead to a faulty assembly of the enzyme and a greater vulnerability to metabolic insult.

Dataset Information

Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson's disease.

Publications

Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson's disease.

Similar Datasets

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