Motivation is affected by oxidative stress, but nutrition can help
Abstract: Higher levels of glutathione in the nucleus accumbens are associated with better and more stable performance on motivation-based tasks. The findings suggest that improvements in accumbal antioxidant function that can be achieved through diet or supplementation may be a feasible approach to increase motivation.
In life, motivation can be the difference between success and failure, goal setting and aimlessness, prosperity and misfortune. Yet getting and staying motivated is often the hardest step, a problem that has fueled much research.
A very small part of that research dealt with the issue of metabolism. “Do differences in brain metabolites affect our ability to motivate?” asks Professor Carmen Sandi from EPFL’s School of Life Sciences. “If this is the case, could dietary interventions that can affect metabolite levels be an effective means of improving motivated performance?”
Sandi’s group, with colleagues at the Nestlé Institute of Health Sciences, has now published a study that sheds the first light on the answer to that question. The researchers focused on an area deep in the brain called the nucleus accumbens, which is known to play a major role in regulating functions such as reward, support, aversion, and not least, 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 exposed to constant oxidative stress, as a result of its metabolism.
What is oxidative stress? As cells “eat” various molecules for fuel, they produce numerous toxic waste products in the form of highly reactive molecules collectively known as “oxidative species.” Of course, cells have a number of mechanisms for removing oxidative species, restoring the cell’s chemical balance. But this battle continues, sometimes this balance is disturbed and we call this disturbance “oxidative stress”.
Connection with glutathione
The brain is then often exposed to 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 most important antioxidant in the brain, a protein called glutathione (GSH), and its relationship with motivation.
“We assessed relationships between metabolites in the nucleus accumbens—a key brain region—and motivated performance,” says Sandi. “We then turned to animals to understand the mechanism and examine the causality between the metabolite found and performance, also proving that nutritional interventions change behavior through this pathway.”
Monitoring of GSH in the nucleus accumbens
First, they used a technique called “proton magnetic resonance spectroscopy,” which can assess and quantify the biochemistry in a specific brain region in a non-invasive manner.
The researchers applied the technique to the nucleus accumbens of both humans and rats to measure GSH levels. They then compared these levels to how well or poorly their human and animal subjects performed on standardized effort-related tasks that measure motivation.
What they found was that higher levels of GSH in the nucleus accumbens were associated with better and more stable performance on motivational tasks.
GSH level and motivation
But correlation does not imply causation, so the team moved on to live experiments with rats given microinjections of GSH blockers, which reduced antioxidant synthesis and levels. The rats now showed less motivation, as reflected in poorer performance in effort-based and reward-based tests.
On the contrary, 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 did better. The effect was “potentially mediated by a cell type-specific shift in glutamatergic inputs to accumbal medium spiny neurons,” the authors write.
Can nutrition or nutritional supplements help with motivation?
“Our study provides new insights into how brain metabolism is linked to behavior and highlights nutritional interventions targeting a key oxidative process as ideal interventions to facilitate exercise endurance,” the authors conclude. The study’s findings “suggest that improving accumbal antioxidant function may be a feasible approach to enhancing motivation.”
“N-acetylcysteine, the dietary supplement we provided in our study, can also be synthesized in the body from its precursor cysteine,” says Sandi. “Cysteine is contained in ‘high protein foods’, such as meat, chicken, fish or seafood. Other lower sources are eggs, whole grain foods like bread and cereal, and some vegetables like broccoli, onions, and legumes.”
“Of course, there are ways other than N-acetylcysteine to increase GSH levels in the body, but how they relate to levels in the brain – and specifically in the nucleus accumbens – is largely unknown. Our study provides proof of principle that dietary N-acetylcysteine can increase GSH levels in the brain and facilitate effortful behavior.”
About this motivation and news from neuroscience research
Original research: Open access.
“Glutathione in the nucleus accumbens regulates reward-driven effort motivation,” John Zalachoras et al. eLife
Glutathione in the nucleus accumbens regulates reward-driven effort motivation
Increasing evidence suggests that mitochondrial function and metabolism in the nucleus accumbens influence motivated performance.
However, the brain is susceptible to excessive oxidative stress resulting from neurometabolic processes, and it is unknown whether antioxidant levels in the nucleus accumbens contribute to motivated performance.
Here we identify the critical role of glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation.
Using proton magnetic resonance spectroscopy (1H-MRS) at ultra-high field in clinical and preclinical populations, we find that higher accumbal GSH levels are highly predictive of better and especially stable performance over time in effort-related tasks.
Causality was established in preclinical in vivo experiments that, first, showed that lowering GSH levels via microinjections of the GSH synthesis inhibitor buthionine sulfoximine into the nucleus accumbens impairs reward-based performance.
In addition, systemic treatment with the GSH precursor N-acetyl-cysteine (NAC) increased accumbal GSH levels and led to enhanced efficacy, potentially mediated by a cell type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close relationship between accumulative GSH levels and an individual’s ability to exert reward-induced effort over time.
They also suggest that improving accumbal antioxidant function may be a feasible approach to enhancing motivation.