Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort
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Evaluation Summary:
This study uses both humans and rats to demonstrate that the level of glutathione in the nucleus accumbens correlates with effortful behaviors. The authors provide causal evidence for glutathione in rats by manipulating enzymes involved in the synthesis of glutathione. Although how exactly glutathione regulates effort-related behavior remains to be clarified, overall, the study gives convincing evidence for an important role of glutathione in nucleus accumbens in regulating the willingness to invest effort to obtain reward or escape an aversive situation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in in vivo experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual’s capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.
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Evaluation Summary:
This study uses both humans and rats to demonstrate that the level of glutathione in the nucleus accumbens correlates with effortful behaviors. The authors provide causal evidence for glutathione in rats by manipulating enzymes involved in the synthesis of glutathione. Although how exactly glutathione regulates effort-related behavior remains to be clarified, overall, the study gives convincing evidence for an important role of glutathione in nucleus accumbens in regulating the willingness to invest effort to obtain reward or escape an aversive situation.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
In this manuscript, Zalachoras and colleagues examined the role of glutathione (GSH) in the nucleus accumbens in effort-related behaviors. First, human participants were subjected to a behavioral task requiring physical efforts in which they are asked to squeeze a handgrip to obtain a monetary reward. The authors then quantified the level of 10 metabolites in the nucleus accumbens (NuAc) using 7T proton magnetic resonance spectroscopy (1H-MRS) and found that the level of GSH positively correlated with successful performance in the task. The authors then turned to rats and examined the causal relationship between GSH and effort-based task performance. First, the authors show that rats with high GSH in NuAc (as measured using ultra-high field 1H-MRS) spent more time moving in a forced swim test than those with …
Reviewer #1 (Public Review):
In this manuscript, Zalachoras and colleagues examined the role of glutathione (GSH) in the nucleus accumbens in effort-related behaviors. First, human participants were subjected to a behavioral task requiring physical efforts in which they are asked to squeeze a handgrip to obtain a monetary reward. The authors then quantified the level of 10 metabolites in the nucleus accumbens (NuAc) using 7T proton magnetic resonance spectroscopy (1H-MRS) and found that the level of GSH positively correlated with successful performance in the task. The authors then turned to rats and examined the causal relationship between GSH and effort-based task performance. First, the authors show that rats with high GSH in NuAc (as measured using ultra-high field 1H-MRS) spent more time moving in a forced swim test than those with low GSH. Furthermore, the authors used a progressive ratio (PR) task in rats, and showed that rats with high NuAc GSH levels exhibited a higher breakpoint, and bilateral injections of an inhibitor of gamma-glutamylcysteine synthetase (BSO), which inhibits the synthesis of GSH, into NAcc lowered a breakpoint than in control animals. Conversely, enhancing GSH synthesis by injecting N-acetyl-cysteine (NAC) into NuAc increased the NAcc GSH level and heightened a breakpoint in the PR task. Finally, the authors performed ex vivo patch-clamp recordings in the NuAc and showed that the amplitudes of miniature excitatory synaptic currents were increased and decreased in direct- and indirect-pathway medium spiny neurons in NuAc.
GSH consists of three amino acids (cysteine, glutamic acid and glycine), and is known as an important antioxidant. The finding that the level of GSH in NuAc correlates with effort-related behaviors is intriguing although the exact mechanism, while discussed in Discussion, remains unclear. The results are presented clearly and the authors make sound discussions.
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Reviewer #2 (Public Review):
Overall, the rodent work gives convincing evidence for an important role of glutathione in nucleus accumbens in regulating the willingness to invest effort to obtain reward or escape an aversive situation. The convergent approach to assess the putative underlying biological mechanisms, is a particularly impressive combination of behaviour (forced swim test, progressive ratio test), MRS, BSO infusions, ex vivo electrophysiology, NAC dietary treatment, chromatography and identification of D1/D2 MSNs.
I would like to see made clearer the link between metabolism in the accumbens and effort-based decision-making. Beyond the basic logic that the nucleus accumbens is important in motivated performance, and that compromised metabolism in any brain region would reduce processing and thus affect any process that is …
Reviewer #2 (Public Review):
Overall, the rodent work gives convincing evidence for an important role of glutathione in nucleus accumbens in regulating the willingness to invest effort to obtain reward or escape an aversive situation. The convergent approach to assess the putative underlying biological mechanisms, is a particularly impressive combination of behaviour (forced swim test, progressive ratio test), MRS, BSO infusions, ex vivo electrophysiology, NAC dietary treatment, chromatography and identification of D1/D2 MSNs.
I would like to see made clearer the link between metabolism in the accumbens and effort-based decision-making. Beyond the basic logic that the nucleus accumbens is important in motivated performance, and that compromised metabolism in any brain region would reduce processing and thus affect any process that is dependent on this particular brain region. Is there a specific mechanism through which metabolism would affect particularly effort-based motivated performance? Would this not hold for other accumbens-dependent processes? How does this relate to for example resource limitation theories for cognitive control in the prefrontal cortex.
Furthermore, there are a number of specific concerns that I have about the paper:
- Lack of specificity of the effects: all manipulations and measurements are only in the nucleus accumbens, but not compared to a control region, so it is unclear whether the
- Lack of generalizability because a male-only population (both human and rodent) is tested
- In the human MRS study, the task cannot dissociate changes in willingness to exert effort from changes in the valuation / motivation, i.e. in the cost-benefit balance of effort and incentive, it is unclear which of these is changed to alter behaviour.
- Statistical analyses consist of many independent tests not corrected for multiple comparisons, that should instead be combined into a single analysis. Furthermore, difference between groups are implied based on the presence/absence of an effect in each group, rather than a direct comparison between these. -
Reviewer #3 (Public Review):
In this manuscript by Zalachoras and colleagues, the authors utilize proton magnetic resonance spectroscopy to investigate the levels of multiple metabolites in the nucleus accumbens of male human subjects during performance of a motivated behavioral task. They discover that glutathione levels are elevated in individuals with the highest motivational performance scores and that these levels directly correlated with effort. Using a similar approach in male rats, the authors confirm a similar relationship between accumbal glutathione levels and motivated behavior. The authors further demonstrate that decreasing or increasing glutathione levels in the nucleus accumbens decreases, or increases motivated behavior in male rats, respectively. Finally, the authors demonstrate that increasing glutathione levels in …
Reviewer #3 (Public Review):
In this manuscript by Zalachoras and colleagues, the authors utilize proton magnetic resonance spectroscopy to investigate the levels of multiple metabolites in the nucleus accumbens of male human subjects during performance of a motivated behavioral task. They discover that glutathione levels are elevated in individuals with the highest motivational performance scores and that these levels directly correlated with effort. Using a similar approach in male rats, the authors confirm a similar relationship between accumbal glutathione levels and motivated behavior. The authors further demonstrate that decreasing or increasing glutathione levels in the nucleus accumbens decreases, or increases motivated behavior in male rats, respectively. Finally, the authors demonstrate that increasing glutathione levels in the brain through dietary supplementation with the cysteine donor N-acetyl-cysteine increases excitatory synaptic connectivity onto subpopulations of accumbal medium spiny neurons in subtly distinct ways with the core region of the structure. The strengths of the manuscript include the translational linkages between humans and the rat experimental system, the bidirectional modulation of glutathione levels, and analysis of synaptic changes in accumbal medium spiny neurons. Collectively these data support an important role for antioxidants in the function of the nucleus accumbens and the regulation of motivated behavior that has broad implications for the use of antioxident supplements in the treatment of disorders in which motivated behaviors are disrupted. However, the study is limited in its analysis of only male human and rodent subjects, leading to the question of whether these findings are sex-specific. Moreover, there is limited evidence to support whether the effects of treatment with antioxidants is temporary or irreversible, and the extent to which changes in synaptic connectivity in the nucleus accumbens also occur within the shell region of this structure, which is known to play an important role in the regulation of motivation.
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