Neurocomputational mechanisms underlying anergia: a bidirectionally translational approach.

Anergia, the reduced propensity to expend effort leading to the avoidance of rewarding activities, is a key symptom of a wide range of psychiatric, neurological and systemic disorders. Despite its prevalence, the neurobiological and computational mechanisms underlying anergia are still lacking. Filling this gap of knowledge could help inform new treatment strategies. We hypothesize that: 1- anergia can be behaviorally and neurally deconstructed into fundamental computational components: a disruption in “perceived effort” exerted towards previously goal-directed activities (now perceived as being more effortful), encoded in the release of glutamate from the ventral hippocampus to a major hub of the reward circuitry, the nucleus accumbens (NAc), or an impairment in “perceived reward-rate” of the environment (now perceived as impoverished), encoded in the release of dopamine to the NAc; 2- chronic stress induces anergia by hijacking the specific neurobiological motifs within the NAc that encode perceived effort and reward-rate; 3- behaviorally distinguishable mechanisms underlying anergia can be translated to stratify depressed patients into behavioral-computational phenotypes; -4 such stratification will help tailoring cognitive-behavioural interventions to patients. By bridging the gap between basic research and clinical application, our study aims to revolutionize the treatment landscape for depression, offering hope to millions worldwide.