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

Opeyemi O Alabi,Michael P Fortunato,Joseph W Kable,Marc Vincent Fuccillo,Mara Robinson,Luigim Vargas Cifuentes,M Felicia Davatolhagh

doi:10.7554/elife.54838

Abstract

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.

Highlights

Goal-directed behaviors are a critical aspect of animal fitness
This work represents an important step in characterizing the genetic contributions to circuit dysfunction for a core neuropsychiatric disease-relevant behavior – how animals choose actions according to cost and benefit. 128 RESULTS Neurexin1α KOs have blunted responses to relative reward outcomes We found that Nrxn1a knockout (KO) mice could perform basic light-guided operant responding with consistent task engagement (Fig.1 - figure supplement 1A-C)
We found that blunting of fast peak dynamics in Nex-Nrxn1αcKO mutants was specific to aspects of reward processing - i.e., while peak slopes had significant correlation to reward history, reward prediction error and comparative choice values in wild-type mice, these outcome-sensitive signal components were absent in mutant striatal population dynamics (Fig.8H)

Summary

Introduction

Goal-directed behaviors are a critical aspect of animal fitness Their implementation engages widespread neural circuits, including cortico-striatal-thalamic loops and midbrain dopaminergic populations. 104 Behavioral abnormalities in Nrxn1α knockout animals include reduced nest building and social memory, increased aggression and grooming, enhanced rotarod learning, and male-specific reductions in operant responding under increasing variable interval responding schedules (Dachtler et al, 2015; Esclassan et al, 2015; Etherton et al, 2009; Grayton et al, 2013) Despite this broad dysfunction, the underlying mechanistic contributions of Nrxn1α to disease-relevant behaviors remain unclear, owing to our poor understanding of the specific computational algorithms and neural circuit implementations for the behavioral functions interrogated by these standard assays. This work represents an important step in characterizing the genetic contributions to circuit dysfunction for a core neuropsychiatric disease-relevant behavior – how animals choose actions according to cost and benefit

Methods

Results

Conclusion