Prefrontal inhibitory mechanisms associated with Putamen activity during valence learning revealed by multimodal fMRI-fMRS

Learning from appetitive and aversive stimuli involves interactions between the prefrontal cortex and subcortical structures. Preclinical and theoretical studies indicate that gamma-aminobutyric acid (GABA) is essential in regulating the relevant neural circuitry. Here, we demonstrate that GABA, the main inhibitory neurotransmitter in the central nervous system, differentially affects how the dorsal anterior cingulate cortex (dACC) interacts with subcortical structures during appetitive and aversive reinforcement learning (RL) in humans. In a large cohort of healthy adults, we combined 7 T magnetic resonance spectroscopy (MRS) with whole-brain functional magnetic resonance imaging (fMRI) while they performed matched appetitive and aversive RL tasks. During appetitive RL, higher baseline GABA concentrations in the dACC were linked to superior learning performance, and greater GABA concentrations change during the task were associated with weaker blood-oxygen-level-dependent (BOLD) responses in the dACC and the putamen. None of these associations occurred during aversive RL, suggesting that dACC GABA selectively shapes cortico-striatal dynamics for appetitive RL, implicating distinct neurochemical mechanisms for appetitive versus aversive reinforcement in humans.