Neurexin Photometry

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 Neurexin1α,
a neuropsychiatric disease-associated synaptic molecule, in value-based
choice paradigms. We found Neurexin1α knockouts exhibited reduced
selection of beneficial outcomes and impaired avoidance of costlier
options. Reinforcement modeling suggested this was driven by deficits in
updating and representation of value. Disruption of Neurexin1α within
telencephalic excitatory projection neurons, but not thalamic neurons,
recapitulated choice abnormalities of global Neurexin1α knockouts.
Furthermore, this selective forebrain excitatory knockout of Neurexin1α
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 Nrxn1α disruption and
changes in value-modulated neural activity, we reveal potential neural
substrates for the pathophysiology of neuropsychiatric disease-associated
cognitive dysfunction.