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

Abstract

Goal-directed behaviors, complex action sequences that maximize reward, are essential for normal function and are significantly impaired across neuropsychiatric disorders. Despite extensive associations between genetic mutations and these brain disorders, the mechanisms by which candidate genes contribute to goal-directed dysfunction remains unclear, owing to challenges in (1) describing aspects of reward processing that drive goal-directed dysfunction, (2) localizing these deficits to specific brain circuits and (3) relating changes in physiology to behavioral alterations. Here we examined mice with mutations in Neurexin1, a presynaptically-localized adhesion molecule with widespread neuropsychiatric dis ease association, in value-based decision-making paradigms. We found that Neurexin1 knockout animals exhibited blunted choice bias towards outcomes associated with greater benefits. Mutant mice were similarly impaired in avoiding costlier, benefit-neutral actions. Analysis of trial-by-trial choice data via reinforcement learning models suggested these behavioral patterns were driven largely by deficits in the updating and representation of choice values. Employing conditional gene ablation and region-specific Cre-recombinase strains, we revealed that Neurexin1 disruption within forebrain excitatory projection neurons, but not thalamic population s, recapitulated most aspects of the whole-brain knockout phenotype. Finally, utilizing in vivo recordings of direct pathway spiny neuron population calcium activity, we demonstrated that selective knockout of Neurexin1 within forebrain excitatory neurons disrupts reward-associated neural signals within striatum, a major site of feedback-based learning. By relating deficits in value-based decision-making to region-specific Nrxn1 disruption and changes in reward-associated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.