Dorsal Striatum Silencing Attenuates Light Self-administration in Mice and Its Relevance to Digital technology-based Disorders

Abstract

Background and aimsSubstance-use addiction models have demonstrated that a progressive transition from reward-guided to habitual and ultimately compulsive behaviour is mediated by a ventral-to-dorsal striatal shift in behavioural control. While symptomatic and neural similarities between substance and digital technology-based disorders have been hypothesised, the causal role of the striatum in the latter remains unknown. We here employ a validated mouse light self-administration paradigm with a loss-of-function approach to determine the role of the dorsal striatum in behavioural persistence towards non-food, non-drug reinforcers. MethodsMice received a control virus or a virus expressing the inhibitory designer receptor (hM4Di) into the dorsal striatum (caudate-putamen). The chemogenetic actuator clozapine N-oxide (CNO) was injected systemically shortly before selected sessions, silencing striatal neuronal firing in vivo in hM4Di-expressing mice. During operant training, lever presses were reinforced by light under fixed-ratio schedules of reinforcement (FR1, FR3, and FR5). ResultsOn initial training days, CNO reduced light self-administration in striatal hM4Di-expressing mice. CNO had a negligible effect in control mice under FR3 and FR5 but attenuated responding in hM4Di mice, which showed response recovery on days without CNO. Linear mixed-effects models confirmed an improvement in light self-administration across days, with a stronger detrimental effect of CNO in hM4Di mice. DiscussionDorsal striatum silencing attenuates light self-administration without impairing response acquisition. Thus, like drug self-administration, light self-administration relies partly on dorsal striatal neurons. Our work bridges the gap between animal models and human neuroimaging studies reporting shared brain mechanisms underlying non-drug and drug habits.