Summary: Higher levels of glutathione in the nucleus accumbens are associated with better and more robust performance in motivation-based tasks. The findings suggest improvements in accumbal anti-oxidant function that can be obtained through diet or supplementation may be a feasible approach to help improve motivation.
In life, motivation can be the difference between success and failure, goal setting and aimlessness, well-being and unhappiness. However, becoming and staying motivated is often the most difficult step, a problem that has prompted much research.
A small portion of that research has examined the question of metabolism. “Do differences in metabolites in the brain affect our capacity for motivation?” asks Professor Carmen Sandi at EPFL’s School of Life Sciences. “If that is the case, could a nutritional intervention that can affect metabolite levels be an effective vehicle for improving motivated performance?”
Sandi’s group, with their colleagues at the Nestlé Health Sciences Institute, have now published a study that sheds the first light on answering that question. The researchers focused on an area deep into the brain called the “nucleus accumbens”, which is known to play a key role in controlling functions such as reward, reinforcement, aversion, and not least, motivation.
Metabolism and oxidative stress in the brain
The idea behind the study is that the brain itself—like all tissues in our body—is subject to constant oxidative stress, as a result of its metabolism.
What is oxidative stress? When a cell “eats” various molecules for fuel, it produces a number of toxic waste products in the form of highly reactive molecules collectively known as “oxidative species”. Of course, cells have several mechanisms to scavenge oxidative species, restoring the cell’s chemical balance. But the battle continues, sometimes that balance is disturbed and that disturbance is what we call “oxidative stress”.
The brain then often experiences excessive oxidative stress from its neurometabolic processes—and the question for researchers is whether antioxidant levels in the nucleus accumbens can affect motivation. To answer that question, scientists looked at the brain’s most important antioxidant, a protein called glutathione (GSH), and its relationship to motivation.
“We evaluated the relationship between metabolites in the nucleus accumbens—a key brain region—and motivated performance,” Sandi said. “We then turned to animals to understand the mechanism and causality of the investigation between metabolites and performance found, proving also that nutritional intervention modifies behavior through this pathway.”
Detecting GSH in the nucleus accumbens
First, they used a technique called “proton magnetic resonance spectroscopy,” which can assess and measure biochemistry in specific areas of the brain in a non-invasive way.
The researchers applied the technique to the nucleus accumbens of both humans and mice to measure GSH levels. They then compared those levels to how well or poorly their human and animal subjects performed on standard effort-related tasks that measured motivation.
What they found was that higher levels of GSH in the nucleus accumbens correlated with better and sustained performance in motivational tasks.
Level and motivation of GSH
But correlation does not imply causation, so the team turned to live experiments with mice given microinjections of GSH blockers, down-regulating the synthesis and levels of antioxidants. Rats now show less motivation, as seen in poorer performance in effort-based tests and reward incentives.
Conversely, when the researchers gave the mice a nutritional intervention with the GSH precursor N-acetylcysteine—which increases GSH levels in the nucleus accumbens—the animals performed better. The effect is “potentially mediated by a cell type-specific shift in glutamatergic input to the accumulating medium spiny neurons,” as the authors wrote.
Can nutrition or supplements help with motivation?
“Our study provides new insights into how brain metabolism relates to behavior and presents nutritional interventions targeting key oxidative processes as ideal interventions to facilitate effortful endurance,” concluded the authors. The study’s findings “suggest that increasing the function of cumulative antioxidants may be a feasible approach to increase motivation.”
“N-acetylcysteine, the nutritional supplement we provided in our study can also be synthesized in the body from its precursor cysteine,” said Sandi. “Cysteine is contained in ‘high protein foods’, such as meat, chicken, fish or seafood. Other sources with lower content are eggs, whole grain foods such as bread and cereal, and some vegetables such as broccoli, onions, and beans.
“Of course, there are other ways beyond N-acetylcysteine to increase GSH levels in the body, but how it relates to levels in the brain—and especially in the nucleus accumbens—is largely unknown. Our study represents proof of principle that N -acetylcysteine nutrition can increase brain GSH levels and facilitate simple behavior.”
About this motivational and neuroscience research news
Author: Press Office
Contact: Press Office – EPFL
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Original Research: Open access.
“Glutathione in the nucleus accumbens regulates the motivation to perform reward incentive efforts,” by Ioannis Zalachoras et al. eLife
Glutathione in the nucleus accumbens regulates the motivation to perform reward incentive efforts
Emerging evidence implicates mitochondrial function and metabolism in the nucleus accumbens in motivated performance.
However, the brain is susceptible to excessive oxidative insult as a result of neurometabolic processes and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is unknown.
Here, we identify an important role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation.
Using proton magnetic resonance spectroscopy (1H-MRS) in ultrahigh fields in both clinical and preclinical populations, we established that higher accumulated GSH levels are highly predictive of better performance, and especially stable performance over time in effort-related tasks.
Causality has been established in preclinical in vivo experiments which, firstly, showed that down-regulating GSH levels by microinjection of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impair performance of effort-based reward incentives.
In addition, systemic treatment with the GSH precursor N-acetyl-cysteine (NAC) increases accumulated GSH levels and leads to improved performance, potentially mediated by a cell type-specific shift in glutamatergic input to accumulated medium spiny neurons. Our data show a close relationship between accumulated GSH levels and an individual’s capacity to exert reward-motivated effort over time.
They also suggest that improving the function of accumbal antioxidants may be a feasible approach to increase motivation.