GABA and Glx distinctively predict motor learning and retention in young and older adults

Gamma aminobutyric acid (GABA) and glutamate are fundamental in neural plasticity. Motor learning is predicted by baseline levels of these metabolites and their modulation in the sensorimotor cortex (SM1), but less is known about the metabolic activity in other areas that support learning, such as the dorsolateral prefrontal cortex (DLPFC), as well as the practice-induced metabolic modulation and age-associated differences. We investigated whether: a) motor learning induces a differential degree of metabolic modulation in the SM1 and DLPFC, b) learning tasks with higher difficulty levels enhance metabolic modulation as compared to those with lower difficulty levels, c) metabolic modulation during motor learning is age dependent, and d) training-induced metabolic modulation may have a differential effect on motor learning and retention. Young (n=25, 12 females) and older (n=21, 10 females) human adults completed a six-day motor learning protocol with Magnetic Resonance Spectroscopy (MRS) scans being administered before, during and after a low- and high task-complexity training condition. We observed a training-induced reduction of SM1 GABA+, regardless of age and task difficulty level, but no significant changes in DLPFC. Neither region showed a significant Glx (combined measure of Glutamate and Glutamine) modulation. In addition, baseline GABA+ levels predicted learning, but this effect was region and task-difficulty dependent. Age-related differences emerged in the prediction of retention, with older adults showing a beneficiary role of task-induced increase in the SM1 inhibitory tone. These results highlight the complexity of metabolic dynamics in learning and retention, showing their dependency on age, brain region and task difficulty.<b>Significance Statement</b> Excitatory and inhibitory metabolites are essential for learning. Although motor learning is linked to reduced GABA levels in the motor cortex, metabolic activity in other learning-related regions remains unclear. It is also unknown whether neuromodulations depend on task difficulty or age. We demonstrate that inhibitory metabolite levels decrease in the motor cortex, but not in the prefrontal cortex, independent of age and task difficulty. Notably, age-related differences emerged in the prediction of retention: in older adults, task-induced increases in SM1 inhibitory tone were associated with better retention performance, whereas no association was observed in young adults. These findings underscore the complex nature of metabolic dynamics underlying motor learning and retention, emphasizing their dependence on age, brain region, and task difficulty.