Summary: Higher levels of glutathione in the nucleus accumbens were associated with better and more stable performance on stimulation-based tasks. The findings suggest that improvements in cumulative antioxidant function that can be obtained through diet or supplementation may be a feasible way to help boost motivation.
In life, motivation can be the difference between success and failure, goal setting and lack of purpose, well-being and unhappiness. However, getting motivated and keeping it going is often the hardest step, and it’s an issue that has prompted a lot of research.
A very small portion of this research has looked at the issue of metabolism. Do differences in metabolites in the brain affect our ability to be motivated? asks Professor Carmen Sandy at the EPFL School of Life Sciences. “If so, could dietary interventions that can influence metabolic levels be an effective way to improve motivated performance?”
Sandy’s group, along with colleagues at the Nestlé Institute of Health Sciences, has published a study that highlights the answer to this question. The researchers focused on a region deep in the brain called the nucleus accumbens, which is known to play a key role in regulating functions such as reward, reinforcement and aversion, not least of which is motivation.
Metabolism and oxidation in the brain
The idea behind the study was that the brain itself – like all tissues in our body – is subjected to constant oxidative stress, as a result of the metabolism process.
What is oxidation? As cells “eat” different molecules for fuel, they produce a number of toxic waste products in the form of highly reactive molecules known collectively as “oxidizing species.” Of course, cells have a number of mechanisms in place to remove oxidative species, restoring the chemical balance of the cell. But this battle is going on, and sometimes that balance is disturbed and that disruption is what we call “oxidative stress.”
Then, the brain is often exposed to excessive oxidative stress from neurotransmitter metabolism, and the question for the researchers was whether levels of antioxidants 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 stimulation.
“We evaluated the relationships between metabolites in the nucleus accumbens – a key brain region – and motivated performance,” says Sandy. “We then turned to animals to understand the mechanism and causation between the metabolite present and performance, further demonstrating that dietary interventions modify behavior through this pathway.”
Trace of GSH in the nucleus accumbens
First, they used a technique called “proton magnetic resonance spectroscopy,” which can non-invasively assess and measure the biochemistry of a specific area of the brain.
The researchers applied this technique to the nucleus accumbens of both humans and rats to measure GSH levels. They then compared those levels to how well or poorly humans and animals performed on standardized effort-related tasks that measure motivation.
What they found is that higher levels of GSH in the nucleus accumbens are associated with better and consistent performance on motivational tasks.
GSH levels and motivation
But correlation does not imply causation, so the team moved on to live experiments with mice that were given microinjections of a GSH blocker, which downregulated the synthesis and levels of the antioxidants. The mice now showed lower motivation, as seen in poor performance on effort- and reward-based tests.
Conversely, when the researchers gave the mice a nutritional intervention with the GSH precursor N-acetylcysteine — which increased GSH levels in the nucleus accumbens — the animals performed better. The effect was “likely mediated by a cell-type-specific shift in glutamate inputs to mesenchymal accumbens spinal neurons,” the authors wrote.
Can Nutrition or Supplementation Help Motivation?
The authors conclude, “Our study provides new insights into how brain metabolism relates to behavior and proposes dietary interventions targeting the key oxidation process as ideal to facilitate stress tolerance.” The results of the study “suggest that improving the function of cumulative antioxidants may be a possible approach to enhancing motivation.”
“N-acetylcysteine, the dietary supplement that we introduced in our study can also be synthesized in the body from cysteine precursors,” says Sandy. “Cysteine is found in ‘protein-rich foods’, such as meat, chicken, fish or seafood. Other sources of lower content are eggs, foods made with whole grains 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 how it relates to levels in the brain – particularly in the nucleus accumbens – is largely unknown. Our study represents proof of principle that dietary N-acetylcysteine can It increases GSH levels in the brain and facilitates stressful behavior.”
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“Glutathione in the nucleus accumbens regulates motivation for reward-inducing effortWritten by Ioannis Zalaschuras et al. eLife
Glutathione in the nucleus accumbens regulates motivation for reward-inducing effort
Emerging evidence suggests that mitochondrial function and metabolism in the nucleus accumbens are involved in the stimulated performance.
However, the brain is susceptible to excessive oxidative insults from neurotransmitters and whether levels of antioxidants in the nucleus accumbens contribute to excitatory performance is unknown.
Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation.
using a proton magnetic resonance spectrometer (1H-MRS) at ultrahigh field in both clinical and preclinical groups, we have demonstrated that higher accumulated GSH levels are significantly predictive of better and particularly consistent performance over time on effort-related tasks.
Causality was determined in in vivo preclinical trials that showed, first, that lowering of GSH levels through microinjections of the GSH synthesis inhibitor buthionine sulfoximine into the nucleus accumbens impairs motivated reward-based performance.
In addition, systemic treatment with the GSH precursor N-acetyl-cysteine (NAC) increased the levels of accumulated GSH and resulted in improved performance, likely mediated by a cell-type-specific shift in glutamate input to mesenchymal spinal neurons accumbens. Our data indicate a close association between accumulated GSH levels and an individual’s ability to exert a reward-motivated effort over time.
They also suggest that improving the function of accumulated antioxidants may be a possible approach to enhancing motivation.