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

eLife

M Felicia Davatolhagh¹  Michael P Fortunato¹  Joseph W Kable²  Mara Robinson²  Luigim Vargas Cifuentes²  Opeyemi O Alabi²  Marc Vincent Fuccillo² 

[1] Neuroscience Graduate Group, Perelman School of Medicine, Philadelphia, United States;Department of Neuroscience, Philadelphia, United States;

关键词: reward learning;    cortex;    value;    striatum;    Neurexin;    reinforcement;   

DOI  :  10.7554/eLife.54838

来源: DOAJ

【 摘 要 】

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 that 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.

【 授权许可】

Unknown