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Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra.

ABSTRACT: The human substantia nigra (SN) is thought to consist of two functionally distinct neuronal populations-dopaminergic (DA) neurons in the pars compacta subregion and GABA-ergic neurons in the pars reticulata subregion. However, a functional dissociation between these neuronal populations has not previously been demonstrated in the awake human. Here we obtained microelectrode recordings from the SN of patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease as they performed a two-alternative reinforcement learning task. Following positive feedback presentation, we found that putative DA and GABA neurons demonstrated distinct temporal dynamics. DA neurons demonstrated phasic increases in activity (250-500 ms post-feedback) whereas putative GABA neurons demonstrated more delayed and sustained increases in activity (500-1000 ms post-feedback). These results provide the first electrophysiological evidence for a functional dissociation between DA and GABA neurons in the human SN. We discuss possible functions for these neuronal responses based on previous findings in human and animal studies.

SUBMITTER: Ramayya AG

PROVIDER: S-EPMC4158808 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra.

Ramayya Ashwin G AG Zaghloul Kareem A KA Weidemann Christoph T CT Baltuch Gordon H GH Kahana Michael J MJ

Frontiers in human neuroscience 20140909

The human substantia nigra (SN) is thought to consist of two functionally distinct neuronal populations-dopaminergic (DA) neurons in the pars compacta subregion and GABA-ergic neurons in the pars reticulata subregion. However, a functional dissociation between these neuronal populations has not previously been demonstrated in the awake human. Here we obtained microelectrode recordings from the SN of patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease as they performe ...[more]

PMID: 25249957

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Project description:BackgroundParkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.ResultsThe gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin) and glutathione-related redox metabolism (GST M3, GST P1, GST O1), including novel redox proteins (SH3BGRL). Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin), as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation), aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism). Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism) and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results.ConclusionUsing an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many more proteins than previously thought. The results point towards a heterogeneous aetiopathogenesis of the disease, including alterations of GSH-related proteins as well as alterations of proteins involved in retinoid metabolism, and they indicate that proteins involved in familial PD may not be differentially regulated in idiopathic Parkinson's disease.

Project description:BACKGROUND:Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS:Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS:At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P???0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time?×?group, P?=?0.002), whereas quantitative susceptibility mapping did not (P?=?0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time?×?group, P???0.084), although both decreased longitudinally (time effect, P???0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P???0.006), but showed a significantly faster increase only in later-stage PD (time?×?group, P?<?0.0001) that correlated with changes in nonmotor symptoms (r?=?0.746, P?=?0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P???0.002), but showed a longitudinal decrease (time?×?group, P?=?0.004) only in later-stage PD that correlated with changes in motor signs (r?=?0.837, P?<?0.001). CONCLUSION:Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Project description:Quantitative proteomic analysis of human post-mortem substantia nigra from patients with Parkinson’s disease (n=3) versus controls (n=3) based on sixplex TMT (TMT6) isobaric labeling which allowed protein simultaneous identification and quantification. Samples were digested and pooled after TMT6 labeling. Peptides were fractionated by OFFGEL electrophoresis (24 fractions). Each peptidic fraction was analyzed in two technical replicates by LC?MS/MS analysis on a LTQ Orbitrap XL mass spectrometer equipped with a NanoAcquity HPLC system. MS data were processed using EasyProtConv (v. 1.21). Peak lists were generated from raw data combining CID and HCD spectra, and submitted to Easyprot (v2.2) which uses Phenyx (GeneBio, Geneva, Switzerland) for protein identification [1]. Searches were conducted against UniProt Swiss-Prot database (08-Feb-2011, 525’207 entries) specifying Homo sapiens taxonomy. Trypsin was selected as the proteolytic enzyme, one missed cleavage was allowed, cysteines carbamidomethylation, TMT6 amino terminus and TMT6 lysine were set as a fixed modification whereas oxidized methionine as variable. The minimum peptide length was five amino acids and precursor error tolerance was 10 ppm. False positive ratios were estimated using a reverse decoy database [3]. Peptide z-scores were set to maintain a false positive peptide ratio below 1%. Proteins with at least two unique distinct peptide sequences were selected and clustered based on shared peptides indistinguishable by MS [4] using Isobar (v 1.3.1) package. The protein entry containing the most peptides was selected as the group reporter. For protein quantification, TMT6 reporter ion intensities were extracted, corrected for isotopic impurities as provided by the manufacturer and each channel was normalized imposing equal median intensity. Only spectra from protein specific peptides not eliminated after outlier filtering were used for quantification. Isobar R package (v 1.3.1.) was used to calculate protein ratios and select statistically significant differentially regulated proteins between the two states.

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Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra.

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Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra.

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