Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
- Gladstone Institute for Neurological Disease, Gladstone Institutes, United States
- Graduate Program in Neuroscience, University of California San Francisco, United States
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, United States
- Department of Nutritional Sciences & Toxicology, University of California Berkeley, United States
- Endocrinology Graduate Program, University of California Berkeley, United States
- UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, United States
- Brain and Mind Centre, Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Australia
- School of Medicine, University of California San Francisco, United States
- College of Science, Northeastern University, United States
- UCSF Department of Physiology, University of California San Francisco, United States
- Graduate Program in Biomedical Sciences, University of California San Francisco, United States
Figures
Figure 1 with 2 supplements
Chronic hM3Dq activation persistently alters the activity of substantia nigra pars compacta (SNc) dopamine neurons.
(A) Graphical illustration summarizing experimental design. Recombinant AAV encoding a conditional allele of the hM3Dq(DREADD)-mCherry was injected bilaterally into the ventral midbrain of 4- to 5-month-old DATIREScre mice. CNO (300 mg/L) or vehicle (2% sucrose in water) was administered ad libitum via drinking water for 2 weeks, and the animals were perfused the next day. Changes in locomotion were assessed with running wheels. The 2 days preceding the start of treatment were used as a measure for baseline locomotion. (B) Representative traces of wheel usage for animals given control vehicle water (top) or CNO water (bottom). Arrows denote start of treatment. Gray background shading indicates dark cycle hours. (C) Mean wheel usage for selected days during the experiment, segregated by light (left), dark (middle), and total (light+dark; right) cycles. n=10 animals/group from 2 independent experiments. (D) Spontaneous firing rate was measured during the first 2 min of whole-cell recordings. n = 21 neurons from 4 vehicle-treated mice and 18 neurons from 5 CNO-treated mice for SN and 11 neurons from 2 vehicle-treated mice and 19 neurons from 2 CNO-treated mice for VTA. (E) Time course of responses to bath application of 1 μM CNO ex vivo measured in current clamp in neurons from vehicle-treated and CNO-treated mice. n = 5 neurons from vehicle-treated mice and 9 neurons from CNO-treated mice for SN and 3 neurons from vehicle-treated mice and 7 neurons from CNO-treated mice. Data indicate mean ± SEM. *p≤0.05, **p<0.01, ***p<0.001 by two-way ANOVA and Holm-Sidak post hoc test (C). *p≤0.05, **p=0.01 by t-test or permutation (nonparametric) analysis (D).
Figure 1—figure supplement 1
Additional behavior data.
(A) (Left) Representative running wheel traces of a DATIREScre mouse injected with AAV-hM3Dq(DREADD)-mCherry following i.p. injection of either saline (left) or clozapine-N-oxide (CNO) (right). Dotted line indicates time of injection. (Right) Average running wheel rotations per minute over 3 hr time period of DATIREScre mice injected with AAV-hM3Dq(DREADD)-mCherry following saline or CNO i.p. injection. (B) Average running wheel rotations per minute over 12 hr light (top) and dark (bottom) cycles for two independent cohorts of DATIREScre mice injected with AAV-hM3Dq(DREADD)-mCherry. CNO (300 mg/L) or vehicle (2% sucrose in water) was administered ad libitum via drinking water for 2 weeks, and the animals perfused the next day. Some data was lost from days 2–6 and 13–14 due to technical issues during Cohort 2. Open circles in light cycle denote incomplete datasets (3 hr). n=5 animals/group/cohort. (C) (Left) Average running wheel rotations per minute over 12 hr light (top) and dark (bottom) cycles for non-injected DATIREScre (CNO alone) mice. (Right) Mean wheel usage for selected days during the experiment, segregated by light (top) or dark (bottom) cycles. n=5 animals/group. (D) (Left) Average running wheel rotations per minute over 12 hr light (top) and dark (bottom) cycles for DATIREScre mice injected with AAV-hM3Dq(DREADD)-mCherry that did not display acute running wheel responses to i.p. of CNO. (Right) Mean wheel usage for selected days during the experiment, segregated by light (top) or dark (bottom) cycles. n=5 animals/group. Data indicate mean ± SEM. *p<0.05 by two-way ANOVA followed by Holm-Sidak post hoc test.
Figure 1—figure supplement 2
Additional electrophysiology data.
(A) Substantia nigra pars compacta (SNc) dopamine (DA) neurons expressing the DREADD and activated for 1 week in vivo showed alterations in clozapine-N-oxide (CNO) responses and overall physiology. Ih magnitude was measured in whole-cell voltage clamp configuration, Vholding = –60 stepping to –120 mV in neurons from vehicle-treated cells vs CNO-treated cells. Firing regularity and input resistance were measured during the first 2 min of whole-cell recordings. Spontaneous action potential (AP) waveforms were compared across groups for threshold membrane potential, peak membrane potential, and duration. Initial membrane potential was measured upon first breaking into the cells for whole-cell recordings. (B) Ventral tegmental area (VTA) DA neurons expressing the DREADD and activated for 1 week in vivo showed alterations in CNO responses and overall physiology. Time course of responses to bath application of 1 μM CNO ex vivo measured in current clamp in neurons from vehicle-treated and CNO-treated mice. Spontaneous firing rate was measured during the first 2 min of whole-cell recordings. Ih magnitude was measured in whole-cell voltage clamp configuration, Vholding = –60 stepping to –120 mV in neurons from vehicle-treated cells vs CNO-treated cells. Firing regularity and input resistance were measured during the first 2 min of whole-cell recordings. Spontaneous AP waveforms were compared across groups for threshold membrane potential, peak membrane potential, and duration. Initial membrane potential was measured upon first breaking into the cells for whole-cell recordings. (C) Example traces of spontaneous firing activity from whole-cell current clamp recordings (I=0 pA) in SNc and VTA neurons from vehicle- and CNO-treated mice. (D) The traces from each neuron tested with 1 μM CNO. These data are summarized in Figure 1E. Each point represents one neuron recorded from 4 vehicle-treated and 5 CNO-treated mice (SN) or 2 vehicle-treated and 2 CNO-treated mice (VTA). *p≤0.05, **p≤0.01, ***p≤0.005 by t-test or permutation (nonparametric) analysis.
Figure 2 with 1 supplement
Chronic activation with AAV-hM3Dq-DREADDs is preferentially toxic to nigrostriatal axons.
DATIREScre mice expressing hM3Dq(DREADD)-mCherry (A–C, E–H) or no virus injection (D) in dopamine (DA) neurons. Example images of TH (A,D,E) and mCherry (B,F) immunoreactivity in striatal sections of mice treated for 2 or 4 weeks with vehicle (left) or clozapine-N-oxide (CNO) (right) via drinking water. DA neuron projection areas in dorsal and ventral striatum are indicated with dotted lines. Quantifications for TH (A,D,E) and mCherry (B,F) optical density at 2 and 4 weeks show preferential loss in CPu. n=8–9 (A), 8 (B), or 3 (D, E, F) animals/group, 3–5 sections/animal. (C,G,H) Images of TH and mCherry (4 weeks only) immunoreactivity in midbrain of vehicle (top) or CNO (bottom) treated mice at 2 or 4 weeks. SN and VTA regions are indicated with dotted lines. (C,G,H) Stereology estimating the number of TH+ or mCherry+ DA neurons. Chronic CNO treatment of hM3Dq(DREADD)-expressing mice shows a significant decrease in both TH and mCherry immunoreactivity and DA neuron number. n=4–5 hemispheres (one per mouse) (C) or 6 hemispheres (two per mouse) (G, H) per group. Scale bars indicate 100 μm in the midbrain and 200 μm in the striatum. Data indicate mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 by two-way ANOVA and Holm-Sidak post hoc test. n.s.: not significant. SN: substantia nigra, VTA: ventral tegmental area, CPu: caudate putamen, NAc-C: nucleus accumbens core, NAc-Sh: nucleus accumbens shell, OT: olfactory tubercle.
Figure 2—figure supplement 1
Additional histological data.
(A) (Top) Example images of TH immunoreactivity in striatal sections of nonresponder mice treated for 2 weeks with vehicle (left) or clozapine-N-oxide (CNO) (right) via drinking water. Dopamine (DA) neuron projection areas in dorsal and ventral striatum are indicated with dotted lines. Quantification for TH optical density shows preferential loss in CPu. n=5 animals/group, 2–4 sections/animal. (B) Example images of TH immunoreactivity in striatal sections of hM3Dq-expressing mice treated for 1 week with vehicle (left) or CNO (right) via drinking water. DA neuron projection areas in dorsal and ventral striatum are indicated with dotted lines. Quantification for TH optical density shows a trend for preferential loss in CPu. n=5 animals/group, 3–5 sections/animal. Scale bars indicate 200 μm. Data indicate mean ± SEM. *p<0.05 by two-way ANOVA and Holm-Sidak post hoc test. n.s.: not significant. CPu: caudate putamen, NAc-C: nucleus accumbens core, NAc-Sh: nucleus accumbens shell, OT: olfactory tubercle.
Figure 3 with 1 supplement
Chronic hM3Dq activation increases baseline calcium in parallel with axonal degeneration.
(A) Transgenic Ai148D mice expressing a Cre-dependent calcium reporter GCaMP6f were crossed with DATIREScre to express GCaMP6f specifically in dopamine (DA) neurons. Mice were injected bilaterally with AAV-DIO-hM3Dq-mCherry and implanted with an optical probe for baseline calcium measurements during a 14-day chronic chemogenetic activation. (B) Representative image of photometry probe placement in mouse midbrain to record from DA neurons co-expressing hM3Dq-mCherry (magenta) and GCaMP6 (cyan). Scale bar is 200 μm. (C) Representative high-magnification images of reporter mCherry (magenta) and GCaMP6 (cyan) co-expression. Scale bar is 10 μm. (D) Representative raw traces of baseline calcium fluorescence in mice treated with vehicle vs clozapine-N-oxide (CNO). (E) Representative isosbestic corrected traces in mice treated with vehicle vs CNO. (F) Baseline calcium fluorescence levels of DA neurons in mice treated with vehicle or CNO for 14 days (gray shaded area) and following wash. n=7 mice/group from 2 independent experiments. Data indicate mean ± SEM. *p<0.05 by two-way ANOVA followed by Holm-Sidak post hoc test.
Figure 3—figure supplement 1
Additional photometry data.
(A) Calcium transient frequency (left) and amplitude (right) in dopamine (DA) neurons in hM3Dq-expressing Ai148D mice treated with vehicle or clozapine-N-oxide (CNO) for 14 days (gray shaded area) and following wash. n=7 mice/group from 2 independent experiments. (B) Distance traveled (left) and percent time spent moving (right) during photometry sessions in mice treated with vehicle or CNO for 14 days (gray shaded area) and following wash. n=3–4 mice/group. Data indicate mean ± SEM. **p<0.01 by two-way ANOVA followed by Holm-Sidak post hoc test. n.s.: not significant.
Figure 4 with 6 supplements
Spatial transcriptomics reveals midbrain dopamine (DA) and striatal target differentially expressed genes (DEGs) altered by chronic DA neuron hyperactivity.
(A) DATIREScre animals that received clozapine-N-oxide (CNO) (CNO alone, n=2 mice) or were injected with AAV-hM3Dq-mCherry and received vehicle (GqVeh, n=3 mice) or CNO (GqCNO, n=3 mice) were treated for 1 week before brains were flash-frozen for spatial transcriptomic analysis. (B) Image of midbrain and striatal sections stained with TH (green), NeuN (purple), and DAPI (blue) shows discs assigned to regions of interest. Inset shows a disc containing two TH+ cell bodies. (C) Expression of dopaminergic and striatal genes is confined to expected spatial regions. Expression of genes involved in DA metabolism decreases with chronic CNO. 2–49 discs were compiled per ventral tegmental area (VTA), and 1–7 discs were compiled per SN. 357–560 capture areas were compiled per CP. The thalamus was selected as a midbrain control region, while white matter tracts (white) and the lateral septal complex (LSX) were used as striatal controls. (D) Principal components analysis of midbrain regions (top) and the caudate putamen (bottom) for GqCNO, GqVeh, and CNO alone groups. (E) The deep learning NEUROeSTIMator model was used to predict neural activity of GqCNO, GqVEH, and CNO alone within the SN and VTA from Visium spatial transcriptomics. Groups were compared using the Kolmogorov-Smirnov (KS) test (see Methods). (F) Hits were used for Enrichr pathway analysis if significant in both GqCNO vs CNO alone and GqCNO vs GqVeh comparisons. Gene rankings for hit analysis were established using fold change score (FCS) and signal-to-noise score (SNS). (G) Volcano plots comparing GqCNO vs GqVeh in the SN, VTA, and CP. Genes highlighted are also significantly altered when comparing GqCNO vs CNO alone. Scale bars indicate 500 µm. Data indicate mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 by one-way ANOVA followed by Holm-Sidak post hoc test.
Figure 4—figure supplement 1
Additional spatial transcriptomic data following chronic hyperactivation.
(A) Anti-TH immunofluorescence of striatal sections processed for spatial transcriptomics demonstrates loss of TH+ fibers in GqCNO sections after 1 week of chronic hyperactivation (white arrows). Scale bars indicate 1 mm. (B) Volcano plots comparing GqCNO vs CNO alone in the SN, VTA, and CP. (C) Bar graphs of individual midbrain and striatal genes of interest. n=2–3 animals/group. Data indicate mean ± SEM. *p<0.05, **p<0.01, ***p<0.001 by one-way ANOVA followed by Holm-Sidak post hoc test. SN: substantia nigra, VTA: ventral tegmental area; CNO: clozapine-N-oxide; CP: caudate putamen.
Figure 4—figure supplement 2
Striatal dopamine (DA) is decreased with chronic activation.
HPLC of CPu dissected from fresh-frozen brain tissue from DATIREScre mice bilaterally injected with AAV-hM3Dq(DREADD)-mCherry and treated with vehicle or clozapine-N-oxide (CNO) water for 1 week (GqVEH and GqCNO) or uninjected DATIREScre treated with CNO water for 1 week (CNO alone). n=2–3 mice per group. Data indicate mean ± SEM. ***p<0.001 by two-way ANOVA followed by Holm-Sidak post hoc test. NE: norepinephrine, DOPAC: 3,4-dihydroxyphenylacetic acid, DA: dopamine, 5HIAA: 5-hydroxyindoleacetic acid, HVA: homovanillic acid, 5HT: 5-hydroxytryptamine or serotonin, 3MT: 3-methoxytyramine.
Figure 4—figure supplement 3
Top differentially expressed genes in the mouse substantia nigra (SN) and ventral tegmental area (VTA).
Heatmaps of the top differentially expressed SN and VTA genes, expressed as the log2 fold score (see Methods). n = 2-3 mice per group.
Figure 4—figure supplement 4
Top differentially expressed genes in the mouse caudate putamen (CP).
Heatmaps of the top differentially expressed CP genes, expressed as the log2 fold score (see Methods). n = 2-3 mice per group.
Figure 4—figure supplement 5
Chronic isradipine treatment does not rescue axonal degeneration.
(A) Experimental paradigm. DATIREScre mice were injected in the left midbrain with saline and the right midbrain with AAV-hM3Dq(DREADD)-mCherry and allowed to recover for 2 weeks. Mice were then subcutaneously implanted with either placebo or isradipine slow-release pellets (3 μg/g/day) and started either vehicle or clozapine-N-oxide (CNO) administration for 2 weeks. (B) Isradipine plasma concentration at the end of the experiment. n=9 animals/group. (C) (Top left) Example images of TH immunoreactivity in striatal sections of mice implanted with placebo or isradipine pellets and treated for 2 weeks with vehicle or CNO via drinking water. (Top right) Quantification for TH optical density in the CPu shows loss with CNO treatment in hM3Dq-injected hemispheres that is not rescued with chronic isradipine treatment. p=0.006 for the interaction between CNO treatment and hM3Dq injection by three-way ANOVA. (Bottom left) Example images of mCherry immunofluorescence in striatal sections of mice implanted with placebo or isradipine pellets and treated for 2 weeks with vehicle or CNO via drinking water. (Bottom right) Quantification for mCherry fluorescence density in the CPu shows loss with CNO treatment in hM3Dq-injected hemispheres that is not rescued with chronic isradipine treatment. n=5–9 hemispheres per group, 2–3 sections/animal. Scale bars indicate 200 μm. Data indicate mean ± SEM. ***p<0.001 by three-way ANOVA followed by Holm-Sidak post hoc test. n.s.: not significant. CPu: caudate putamen.
Figure 4—figure supplement 6
Assessment of mouse differentially expressed genes (DEGs) in human Parkinson’s disease (PD) and control substantia nigra pars compacta (SNc) samples.
Heatmap of normalized gene expression (per region of interest [ROI]) values from GeoMx spatial transcriptomic analysis of human SNpc ventral tier dopamine neurons (TH+) within (A) 51 DEGs and (B) additional genes of interest identified within the mouse model. ‘Limma voom’ methodology was used to assess differential gene expression between control and PD samples. PMD, postmortem delay; DV200, RNA integrity number equivalent. (C) Bar graphs of individual midbrain genes of interest in mouse and PD samples. n = 2-3 mice per group and 10 control and 8 early PD samples. Data indicate mean ± SEM.
Author response image 1
Violin plot of DA neuron proportions sampled within the vulnerable SNV (deconvoluted RCTD method used in unmasked tissue sections of the SNV).
Control and early PD subjects.
Tables
Table 1
Pathway analyses for the ventral tegmental area (VTA), substantia nigra (SN), and caudate putamen (CP) following chronic hyperactivation.
Gene Ontology Molecular Function and Biological Process terms for differentially expressed genes in the VTA, SN, and CP generated with the Enrichr webtool.
| VTA | ||
|---|---|---|
| Index | GO Molecular Function 2023 | p-Value |
| 1 | GTP Binding (GO:0005525) | 0.00002637 |
| 2 | Syntaxin Binding (GO:0019905) | 0.00005402 |
| 3 | Guanyl Ribonucleotide Binding (GO:0032561) | 0.00006568 |
| 4 | Nuclear Receptor Coactivator Activity (GO:0030374) | 0.0005911 |
| 5 | Purine Ribonucleoside Triphosphate Binding (GO:0035639) | 0.001174 |
| Index | GO Biological Process 2023 | p-Value |
| 1 | Chemical Synaptic Transmission (GO:0007268) | 0.00000141 |
| 2 | Synaptic Vesicle Exocytosis (GO:0016079) | 0.0000152 |
| 3 | Anterograde Trans-Synaptic Signaling (GO:0098916) | 0.00002437 |
| 4 | Response To Cytokine (GO:0034097) | 0.00005223 |
| 5 | Response To Interferon-Beta (GO:0035456) | 0.00006911 |
| SN | ||
| Index | GO Molecular Function 2023 | p-Value |
| 1 | Phosphatase Activator Activity (GO:0019211) | 0.001131 |
| 2 | Tubulin Binding (GO:0015631) | 0.002579 |
| 3 | Calcium Channel Regulator Activity (GO:0005246) | 0.005332 |
| 4 | Microtubule Binding (GO:0008017) | 0.005412 |
| 5 | Alpha-Tubulin Binding (GO:0043014) | 0.005618 |
| Index | GO Biological Process 2023 | p-Value |
| 1 | Positive Regulation Of Transporter Activity (GO:0032411) | 8.673E-06 |
| 2 | Establishment Of Spindle Orientation (GO:0051294) | 0.0001492 |
| 3 | Neuron Projection Morphogenesis (GO:0048812) | 0.0009083 |
| 4 | Long-Term Memory (GO:0007616) | 0.001571 |
| 5 | Vesicle Transport Along Microtubule (GO:0047496) | 0.001903 |
| CP | ||
| Index | GO Molecular Function 2023 | p-Value |
| 1 | Protein Phosphatase 2A Binding (GO:0051721) | 0.007033 |
| 2 | Histone Deacetylase Binding (GO:0042826) | 0.01734 |
| 3 | Calcium Channel Regulator Activity (GO:0005246) | 0.01761 |
| 4 | Protein Phosphatase Binding (GO:0019903) | 0.02563 |
| 5 | Arachidonate-CoA Ligase Activity (GO:0047676) | 0.0272 |
| Index | GO Biological Process 2023 | p-Value |
| 1 | DNA Deamination (GO:0045006) | 0.001908 |
| 2 | Positive Regulation Of Mitotic Cell Cycle Phase Transition (GO:1901992) | 0.005059 |
| 3 | Positive Regulation Of G2/M Transition Of Mitotic Cell Cycle (GO:0010971) | 0.00588 |
| 4 | Positive Regulation Of Cell Cycle G2/M Phase Transition (GO:1902751) | 0.007645 |
| 5 | Secondary Alcohol Biosynthetic Process (GO:1902653) | 0.007645 |
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background (Mus musculus, male) | DATIREScre | The Jackson Laboratory | RRID:IMSR_JAX:006660 | |
| Strain, strain background (Mus musculus, male) | Ai148D | The Jackson Laboratory | RRID:IMSR_JAX:030328 | |
| Antibody | Anti-tyrosine hydroxylase (rabbit polyclonal) | Millipore Sigma | RRID:AB_390204 | 1:1000 (IF, DAB), 1:100 (Visium) |
| Antibody | Anti-DsRed (rabbit monoclonal) | Takara | RRID:AB_3083500 | 1:1000 (IF, DAB) |
| Antibody | Anti-NeuN (mouse monoclonal) | Millipore Sigma | RRID:AB_2298772 | 1:200 (Visium) |
| Antibody | Anti-mCherry (chicken polyclonal) | Abcam | RRID:AB_2722769 | 1:200 (Visium) |
| Antibody | Anti-mouse Alexa Fluor 647 (goat polyclonal) | Thermo Fisher | RRID:AB_2535804 | 1:200 (Visium) |
| Antibody | Anti-rabbit Alexa Fluor 488 (goat polyclonal) | Thermo Fisher | RRID:AB_2576217 | 1:500 (IF), 1:200 (Visium) |
| Antibody | Anti-rabbit Alexa Fluor 594 (goat polyclonal) | Thermo Fisher | RRID:AB_2534095 | 1:500 (IF) |
| Antibody | Anti-chicken Alexa Fluor 594 (goat polyclonal) | Thermo Fisher | RRID:AB_2534099 | 1:200 (Visium) |
| Antibody | Anti-rabbit Biotinylated (goat polyclonal) | Vector Laboratories | RRID:AB_2313606 | 1:300 (DAB) |
| Recombinant DNA reagent | rAAV8-hSyn-DIO-hM3Dq-mCherry | UNC Vector Core, AddGene | RRID:Addgene_44361 | Diluted to 4.6e12 mol/mL |
| Commercial assay or kit | Vectastain ABC-HRP Kit, Peroxidase (Rabbit IgG) | Vector Laboratories | PK-4001 | |
| Commercial assay or kit | Visium Spatial Gene Expression (v1) | 10x Genomics | 1000215, 1000187, 1000193, 1000200 | |
| Commercial assay or kit | GeoMx Digital Spatial Profiler | Nanostring | RRID:SCR_021660 | |
| Chemical compound, drug | Clozapine-N-oxide | Tocris Bioscience | 4936 | 300 mg/L via drinking water |
| Chemical compound, drug | Isradipine slow-release pellets | Innovative Research of America | Custom pellets; isradipine supplied by Thermo Fisher (J63920.MF) | 3 μg/g/day release |
| Software, algorithm | EthoVision XT | Noldus | RRID:SCR_000441 | Version 10 |
| Software, algorithm | Wheel Analysis Software | Med Associates | SOF-861 | |
| Software, algorithm | Enrichr | Sei et al., 2023; Chen et al., 2013; Kuleshov et al., 2016 | RRID:SCR_001575 | |
| Software, algorithm | Space Ranger | 10x Genomics | RRID:SCR_023571 | |
| Software, algorithm | Loupe Browser | 10x Genomics | RRID:SCR_018555 | Version 5 |
| Software, algorithm | Stereo Investigator | MBF Bioscience | RRID:SCR_024705 | |
| Software, algorithm | Synapse | TDT | RRID:SCR_006307 | |
| Software, algorithm | GeoMx NGS analysis pipeline | Illumina | RRID:SCR_011881 | Version 2.0.21 |
Table 2
Demography of the human postmortem cohort assayed by GeoMx.
| Group | Gender (M/F) | Age at death (years) | Postmortem delay (hr) | DV200 |
|---|---|---|---|---|
| Aged healthy controls | 3/7 | 92.0 (5.75) | 25 (8.25) | 28.9 (16.4) |
| Early PD | 5/3 | 73.5 (12)† | 17.5 (13.5)* | 28.3 (9.10) |
-
Values are presented as median (IQR). The comparison of age at death, postmortem delay, and DV200 between groups was made using the Welch’s two-sample t-test. The comparison of gender between groups was made using the chi-square test.
-
*
p<0.05.
-
†
p<0.001.
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Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
eLife 13:RP98775.
https://doi.org/10.7554/eLife.98775.3
