Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction

Goal-directed behaviors are essential for normal function and significantly impaired in neuropsychiatric disorders. Despite extensive associations between genetic mutations and these disorders, the molecular contributions to goal-directed dysfunction remain unclear. We examined mice with constitutive and brain region-specific mutations in Neurexin1 alpha, a neuropsychiatric disease-associated synaptic molecule, in value-based choice paradigms. We found Neurexinla knockouts exhibited reduced selection of beneficial outcomes and impaired avoidance of costlier options. Reinforcement modeling suggested that this was driven by deficits in updating and representation of value. Disruption of Neurexin1 alpha within telencephalic excitatory projection neurons, but not thalamic neurons, recapitulated choice abnormalities of global Neurexinla knockouts. Furthermore, this selective forebrain excitatory knockout of Neurexinla perturbed value-modulated neural signals within striatum, a central node in feedback-based reinforcement learning. By relating deficits in value-based decision-making to region-specific Nrxn1 alpha disruption and changes in value-modulated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.