Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort
- Laboratory of Behavioral Genetics (LGC), Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, United States
- Nestlé Institute of Health Sciences, Nestlé Research, Société des Produits Nestlé SA, Vers-chez-les-Blanc, Switzerland
- Animal Imaging and Technology Core (AIT), Center for Biomedical Imaging (CIBM), EPFL, Switzerland
Figures
Figure 1 with 2 supplements
Glutathione (GSH) levels in the nucleus accumbens are associated with the number of successful trials on an effort-based motivation task.
(a) Schematic depiction of GSH metabolic pathways. GSH or γ-L-glutamyl-L-cysteinylglycine, is a tripeptide, that can exist in a reduced (GSH) or in an oxidized (Glutathione disulfide, GSSG) state. …
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Figure 1—source data 1
Spectroscopy on human raw data and statistical analysis.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig1-data1-v1.xlsx
Figure 1—figure supplement 1
Glutathione (GSH) levels in the nucleus accumbens are not associated with the number of successful trials for lower rewards (0.5 CHF and 0.2 CHF).
(a) Region of interest in the human brain (i.e. nucleus accumbens) and examples of metabolites spectra. (b) Matrix showing all pairwise correlations between metabolites of interest and the number of …
Figure 1—figure supplement 2
Representative scans and trace from the human occipital lobe.
(a) Region of interest in the human brain (occipital lobe) and (b) example of metabolite spectra in the same region.
Figure 2 with 1 supplement
Rats differing in accumbal glutathione (GSH) levels show differences in immobility in the forced swim test (FST).
(a) Experimental design: Upon arrival to the facilities, rats were allowed to acclimatize to the conditions and were handled to habituate to the experimenters. Then they were tested in the elevated …
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Figure 2—source data 1
Raw data Figure 2.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig2-data1-v1.xlsx
Figure 2—figure supplement 1
Rats differing in accumbal glutathione (GSH) levels show no significant differences in GSH levels in medial prefrontal cortex (mPFC).
(a) Plot showing GSH levels in the mPFC of low/high GSH (L/H-GSH) groups (median-split by GSH levels in the nucleus accumbens; unpaired two-tailed t-test, t(33) = 0.74, p=0.47; Bayesian independent …
Figure 3 with 1 supplement
High glutathione (H-GSH) levels in nucleus accumbens are associated with an improvement in progressive ratio (PR) test performance.
(a) Timeline showing the experimental design. After initial acclimatization, handling, and behavioral characterization for anxiety and exploratory behavior, rats were placed in reversed light-dark …
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Figure 3—source data 1
Raw data Figure 3.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig3-data1-v1.xlsx
Figure 3—figure supplement 1
High accumbal glutathione (GSH) levels affect the probability to get a higher breakpoint and the persistence of nosepoking over time.
(a) High GSH (H-GSH) and low GSH (L-GSH) rats showed no significant differences in medial prefrontal cortex (mPFC) GSH levels measured by high-performance liquid chromatography (unpaired two-tailed …
Figure 4 with 1 supplement
Intra-accumbal administration of buthionine sulfoximine (BSO) impairs progressive ratio (PR) performance.
(a) Cannulated rats were habituated for 10 days in reversed light-dark cycle during their recovery from surgery. Subsequently, they were trained in a fixed ratio 1 schedule for a total of six …
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Figure 4—source data 1
Raw data Figure 4.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig4-data1-v1.xlsx
Figure 4—figure supplement 1
Accumbal buthionine sulfoximine (BSO) infusion decreases the probability of reaching higher breakpoints in progressive ratio (PR) task.
(a) No significant differences were observed in the percentage of time spent in the center of the open field (OF; unpaired two-tailed t-test, t(18) = 0.60, p=0.56; Bayesian independent samples …
Figure 5 with 1 supplement
N-acetyl-cysteine (NAC) systemic treatment increases glutathione (GSH) levels in nucleus accumbens and ameliorates progressive ratio (PR) task accomplishment.
(a) Timeline of the experiment. After initial habituation, handling, and behavioral characterization for anxiety, rats were placed in reverse light-dark cycle and trained in an FR1 schedule. Once …
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Figure 5—source data 1
Raw data Figure 5.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig5-data1-v1.xlsx
Figure 5—figure supplement 1
N-acetyl-cysteine (NAC) treatment affects the probability of obtaining a higher breakpoint and persistence of nosepoking over the time but does not change body weight or exploration levels.
(a) During operant conditioning training, no significant differences were observed between vehicle (Veh)- and NAC-treated groups (two-way repeated measures ANOVA, treatment: F(1,19) = 1.27, p=0.27, …
Figure 6 with 1 supplement
N-acetyl-cysteine (NAC) treatment affects excitatory inputs onto medium spiny neurons (MSNs) in a cell-type-specific manner.
(a) Experimental timeline for ex vivo electrophysiological recordings in NAC-treated rats. (b–c) Confocal micrographs showing neurons in the nucleus accumbens core filled with biocytin during …
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Figure 6—source data 1
Raw data Figure 6.
- https://cdn.elifesciences.org/articles/77791/elife-77791-fig6-data1-v1.xlsx
Figure 6—figure supplement 1
N-acetyl-cysteine (NAC) treatment does not affect medium spiny neuron (MSN) intrinsic excitability.
(a) Lack of significant differences in cell passive and active properties of nucleus accumbens (NuAc) core dopamine receptor type 1-MSNs (D1-MSNs) from vehicle (Veh)- and NAC-treated rats: input …
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background (Wistar, male) | Rats | Charles River, L’Arbresle, France | RRID:RGD_2312504 | |
| Antibody | Anti-NeuN (rabbit polyclonal) | Millipore | Cat. #:ABN78 RRID:AB_10807945 | 1:1000 |
| Antibody | Anti-cleaved caspase-3 (rabbit polyclonal) | Cell Signaling Technology | Cat. #:9661 RRID:AB_2341188 | 1:200 |
| Antibody | Anti-mouse Alexa Fluor 488 (goat polyclonal) | Thermo Fisher Scientific | Cat. #:A-11029 RRID:AB_2534088 | 1:1000 |
| Antibody | Anti-rabbit Alexa Fluor 488 (donkey polyclonal) | Thermo Fisher Scientific | Cat. #:A-21206 RRID:AB_2535792 | 1:1000 |
| Peptide, recombinant protein | Streptavidin, Alexa Fluor 488 conjugate | Thermo Fisher Scientific | Cat. #:S‐11223 | 1:500 |
| Commercial assay or kit | RNAscope Fluorescent Multiplex Reagent Kit | ACD, Bio-Techne | Cat. #:320850 | probes: Rn-Drd1a-C2 no.317031, Rn-Drd2-C1 no.315641 |
| Chemical compound, drug | Biocytin hydrochloride | Sigma-Aldrich | Cat. #:B1758 CAS No:98930-70-2 | |
| Chemical compound, drug | Tetrodotoxin | Latoxan | Cat. #:L8503 CAS No:4368-28-9 | |
| Chemical compound, drug | Picrotoxin | abcam | Cat. #:ab120315 CAS No:124-87-8 | |
| Chemical compound, drug | N-acetyl-cysteine (NAC) | Sigma-Aldrich | Cat. #:A9165 CAS No:616-91-1 | |
| Chemical compound, drug | L-Buthionine-sulfoximine (BSO) | Sigma-Aldrich | Cat. #:B2515 CAS No:83730-53-4 | |
| Chemical compound, drug | L-Glutathione (GSH) | Sigma-Aldrich | Cat. #:G4251 CAS No:70-18-8 | |
| Chemical compound, drug | 4′,6-Diamidino-2-phenyl-indol -dihydrochlorid | Sigma-Aldrich | Cat. #:D9542 CAS No: 28718-90-3 | |
| Software, algorithm | GraphPad Prism 9 | GraphPad Software | RRID:SCR_002798 | |
| Software, algorithm | pClamp 10 | Molecular Devices, LLC | RRID:SCR_011323 | |
| Software, algorithm | Mini Analysis Program 6.0.3 | Synaptosoft Inc | RRID:SCR_002184 | |
| Software, algorithm | QuPath | PMID:29203879 | RRID:SCR_018257 | |
| Other | 1H-MRS Magnetom 7T/68 cm head | Siemens, Erlangen, Germany | Human spectroscopy | |
| Other | 1H-MRS horizontal 9.4T/31 cm | Magnex Scientific, Abingdon, UK | Rodent spectroscopy |
