Regional Striatal Cholinergic Involvement in Human Behavioural Flexibility

Abstract

Animal studies have shown that the striatal cholinergic system plays a role in behavioural flexibility but, until recently, this system could not be studied in humans due to a lack of appropriate non-invasive techniques. Using proton magnetic resonance spectroscopy (1H-MRS) we recently showed that the concentration of dorsal striatal choline (an acetylcholine precursor) changes during reversal learning (a measure of behavioural flexibility) in humans. The aim of the present study was to examine whether regional average striatal choline was associated with reversal learning. We measured choline at rest in both the dorsal and ventral striatum using 1H-MRS and examined its relationship with performance on a probabilistic learning task with a reversal component. Task performance was described using a simple reinforcement learning model that dissociates the contributions of positive and negative prediction errors to learning. Average levels of choline in the dorsal striatum were associated with performance during reversal, but not during initial learning. Specifically, lower levels of choline in the dorsal striatum were associated with a lower number of perseverative trials. Moreover, choline levels explained inter-individual variance in perseveration over and above that explained by learning from negative prediction errors. These findings suggest that the dorsal striatal cholinergic system plays an important role in behavioural flexibility, in line with evidence from the animal literature and our previous work in humans. Additionally, this work provides further support for the idea of measuring choline with 1H-MRS as a non-invasive way of studying human cholinergic neurochemistry.\n\nSIGNIFICANCE STATEMENTBehavioural flexibility is a crucial component of adaptation and survival, as well as everyday living. Evidence from the animal literature shows the striatal cholinergic system is fundamental to reversal learning, a key paradigm for studying behavioural flexibility. However, this system remains understudied in humans, largely due to a lack of non-invasive techniques. Using proton magnetic resonance spectroscopy (1H-MRS), we showed that choline levels at rest in the dorsal striatum are associated with individual differences in performance specifically during reversal learning. These novel findings help to bridge the gap between animal studies of the striatal cholinergic system and human studies of basal ganglia function, by demonstrating the importance of cholinergic function in the dorsal striatum in human behavioural flexibility. Importantly, the methods described here can not only be applied to furthering our understanding of healthy human neurochemistry, but can also be applied to extending our understanding of cholinergic disorders.