DOPAMINE CIRCUIT DYSFUNCTION LINKS MOTIVATIONAL DEFICITS IN A 22Q11.2 DELETION GENETIC RISK MODEL OF SCHIZOPHRENIA

Negative symptoms including avolition, anhedonia, and asociality represent among the most disabling and treatment-resistant features of schizophrenia. A central question is whether these motivational deficits reflect primary disruption of mesolimbic dopamine computations that normally energize reward-seeking behavior, including pursuit of social rewards. We tested this hypothesis in LgDel mice, a 22q11.2 deletion model associated with high schizophrenia risk.
We quantified motivation for both nonsocial and social rewards using behavioral assays that dissociate preference and consumption from effort allocation. We then linked these behaviors to dopamine dynamics within the mesolimbic circuit using in vivo photometry and electrophysiology.
LgDel mice showed consistent motivational deficits across reward domains. For nonsocial rewards, they exhibited reduced sucrose preference and decreased willingness to work for palatable food under escalating effort demands. For social rewards, LgDel mice showed impaired social engagement and reduced motivation to work for conspecific access across both fixed- and progressive-ratio schedules. Circuit-level analyses revealed convergent dopamine dysfunction: nucleus accumbens photometry during social interaction showed blunted dopamine release dynamics, while ventral tegmental area Neuropixels recordings revealed altered neuronal activity and impaired encoding of behaviorally relevant variables during free social behavior.
These findings support a model whereby 22q11.2 deletion causes mesolimbic dopamine hypofunction that attenuates motivated behavior across reward types, providing a mechanistic link from genetic risk to negative symptom-relevant behavioral deficits.