Motivation facilitates overcoming the cost of effortful actions to attain desired outcomes and is key to achievement and well-being. Importantly, there are substantial differences in motivated behavior among healthy individuals, manifested as variations in the engagement in effortful activities and in differences in brain activity. Motivational deficits – such as apathy, anhedonia, or anergia- are prevalent in many brain pathologies. Therefore, unveiling the neurobiological mechanisms underlying individual differences in motivation can help develop novel interventions to boost effortful performance.
A great deal of work in both rodents and humans highlights the nucleus accumbens (NuAc) – a main component of the ventral striatum – as a critical node of the brain’s reward and motivation circuitries.
Emerging evidence underscores a key role for accumbal mitochondrial function and metabolism in the regulation of motivated behavior and vulnerability to develop stress-induced depressive-like behaviors.
Recent work in humans using proton magnetic resonance spectroscopy (1H-MRS) focusing on the components of the glutamate/GABA-glutamine cycle has shown that glutamine levels, and particularly, an increased glutamine-to-glutamate ratio in the NuAc predict both, a higher performance related to task endurance and a lower effort perception in a physical effort-based motivated task. Glutamine is the main precursor for the synthesis of glutamate, a building block for the production of glutathione. Glutathione is a tripeptide essential for several cellular functions and the most prominent antioxidant in the brain. It seems, therefore, plausible to hypothesize that GSH levels in the NuAc may be related to the capacity to exert incentivized effort.
What is oxidative stress?
As cells “eat” various molecules for fuel, they produce a number of toxic waste products in the form of highly reactive molecules collectively known as “oxidative species.” Of course, cells have a number of mechanisms in place to clear oxidative species out, restoring the cell’s chemical balance. But that battle is ongoing, sometimes that balance is disturbed and that disturbance that’s what we call “oxidative stress.”
Motivation is affected by oxidative stress, nutrition can help
The researchers applied the technique to the nucleus accumbens of both humans and rats to measure the levels of Glutathione. They then compared those levels to how well or poorly their human and animal subjects performed in standardized, effort-related tasks that measure motivation.
What they found was that higher levels of GSH in the nucleus accumbens correlated with better and steady performance in the motivation tasks.
Glutathione levels and motivation
But correlation does not imply causation, so the team moved on to live experiments with rats that were given micro-injections of a GSH blocker, downregulating the synthesis and levels of the antioxidant. The rats now showed less motivation, as seen in a poorer performance in effort-based, reward-incentivized tests.
On the contrary, when the researchers gave rats a nutritional intervention with the Glutathione precursor N-acetylcysteine , which increased glutathione levels in the nucleus accumbens — the animals performed better. The effect was “potentially mediated by a cell-type specific shift in glutamatergic inputs to accumbal medium spiny neurons,” as the authors write.
Can nutrition or supplements help motivation?
The study provides novel insights on how brain metabolism relates to behavior and puts forward nutritional interventions targeting key oxidative processes as ideal interventions to facilitate effortful endurance. The study’s findings “suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.”
N-acetylcysteine, the nutritional supplement that we gave in the study can also be synthesized in the body from its precursor cysteine. 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 breads and cereals, and some vegetables such as broccoli, onions, and legumes.
The study represents a proof of principle that dietary N-acetylcysteine can increase brain glutathione levels and facilitate effortful behavior.
Eva Ramos-Fernández, Ioannis Zalachoras, Fiona Hollis, Laura Trovo, João Rodrigues, Alina Strasser, Olivia Zanoletti, Pascal Steiner, Nicolas Preitner, Lijing Xin, Simone Astori, Carmen Sandi (November 8, 2022). Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort. eLife. Retrieved from : https://elifesciences.org/articles/77791
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