Summary: Higher levels of glutathione in the nucleus accumbens correlated with better and more stable performance in motivation-based tasks. The results suggest that improvements in accumulated antioxidant function that can be gained through diet or supplementation may be a feasible approach to help boost motivation.
In life, motivation can mean the difference between success and failure, goal setting and goallessness, well-being and unhappiness. And yet, getting and staying motivated is often the most difficult step, an issue that has prompted much research.
A very small part of this research has looked at the issue of metabolism. “Do metabolite differences in the brain affect our ability to motivate? asks Professor Carmen Sandi of EPFL’s Faculty of Life Sciences. “If so, could nutritional interventions that can affect metabolite levels be an effective vehicle for improving motivated performance?”
Sandi’s group, along with colleagues at the Nestlé Institute of Health Sciences, has just published a study that sheds the first light to answer this question. The researchers focused on a deep area of the brain called the “nucleus accumbens”, which is known to play a major role in regulating functions such as reward, reinforcement, aversion and, above all, motivation.
Metabolism and oxidative stress in the brain
The idea behind the study was that the brain itself, like all tissues in our body, is under constant oxidative stress, due to its metabolism.
What is oxidative stress? When cells “eat” various molecules for fuel, they produce a number of toxic waste products in the form of highly reactive molecules collectively known as “oxidant species”. Of course, cells have a number of mechanisms in place to remove oxidative species, thereby restoring the cell’s chemical balance. But this battle is permanent, sometimes this balance is disturbed and this disturbance is what we call “oxidative stress”.
The Glutathione Connection
The brain is then often under excessive oxidative stress due to its neurometabolic processes – and the question for the researchers was whether antioxidant levels in the nucleus accumbens could affect motivation. To answer the question, scientists looked at the brain’s most important antioxidant, a protein called glutathione (GSH), and its relationship to motivation.
“We assessed the relationships between metabolites in the nucleus accumbens – a key region of the brain – and motivated performance,” says Sandi. “We then turned to animals to understand the mechanism and probe the causality between the found metabolite and performance, also proving that nutritional interventions alter behavior through this pathway.”
Tracking of GSH in the nucleus accumbens
First, they used a technique called “proton magnetic resonance spectroscopy,” which can assess and quantify biochemistry in a specific brain region noninvasively.
The researchers applied the technique to the nucleus accumbens of humans and rats to measure GSH levels. They then compared these levels to the performance or poor performance of their human and animal subjects on standardized effort-related tasks that measure motivation.
What they found was that higher levels of GSH in the nucleus accumbens correlated with better and consistent performance on motivational tasks.
GSH levels and motivation
But correlation doesn’t imply causation, so the team moved on to live experiments with rats that received microinjections of a GSH blocker, down-regulating the synthesis and levels of the antioxidant. The rats now showed less motivation, as evidenced by poorer performance in the effort-based and reward-prompted tests.
In contrast, when the researchers gave the rats a nutritional intervention with the GSH precursor, N-acetylcysteine, which increased GSH levels in the nucleus accumbens, the animals performed better. The effect was “potentially mediated by a cell type-specific change in glutamatergic inputs to accumbal medium spiny neurons,” as the authors write.
Can nutrition or supplements help with motivation?
“Our study provides new insights into the relationship between brain metabolism and behavior and suggests nutritional interventions targeting the key oxidative process as ideal interventions to facilitate endurance exercise,” the authors conclude. The results of the study “suggest that improving accumulated antioxidant function may be a feasible approach to boosting motivation.”
“N-acetylcysteine, the nutritional supplement we gave in our study, can also be synthesized in the body from its precursor, cysteine,” Sandi explains. “Cysteine is found in ‘high protein foods’ such as meat, chicken, fish or seafood. Other low sources are eggs, whole grain foods such as bread and cereals, and some vegetables such as broccoli, onions and legumes.
“Of course, there are ways other than N-acetylcysteine to increase GSH levels in the body, but their relationship to levels in the brain – and particularly in the nucleus accumbens – is largely unknown. Our study represents a proof-of-principle that dietary N-acetylcysteine can increase GSH levels in the brain and facilitate effortful behavior.
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Original research: Free access.
“Glutathione in the nucleus accumbens regulates the motivation to exert reward-motivated effort”, by Ioannis Zalachoras et al. eLife
Glutathione in the nucleus accumbens regulates motivation to exert reward-motivated effort
Emerging evidence implicates mitochondrial function and metabolism in the nucleus accumbens in motivated performance.
However, the brain is vulnerable to excessive oxidative insult resulting from neurometabolic processes and it is unknown whether antioxidant levels in the nucleus accumbens contribute to motivated performance.
Here we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation.
Use of proton magnetic resonance spectroscopy (1H-MRS) at ultra-high field in clinical and preclinical populations, we establish that higher cumulative GSH levels are highly predictive of better and particularly stable performance over time in effort-related tasks.
Causality was established in preclinical in vivo experiments which, first, showed that downregulation of GSH levels by microinjections of the GSH synthesis inhibitor buthionine sulfoximine into the nucleus accumbens impaired performance. incentives for effort-based rewards.
Furthermore, systemic treatment with the GSH precursor, N-acetyl-cysteine (NAC), increased cumulative GSH levels and led to improved performance, potentially mediated by a cell type-specific change in inputs. glutamatergic cells to the accumal medium spiny neurons. Our data indicate a strong association between cumulative GSH levels and the individual’s ability to exert reward-motivated effort over time.
They also suggest that improving accumulated antioxidant function may be a feasible approach to boosting motivation.
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