Frontostriatal Circuit Dysfunction Leads to Cognitive Inflexibility in Neuroligin-3 R451C Knockin Mice

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2024 Mar 8

PMID 38459194

Authors

Shen Lin

Cui-Ying Fan

Hao-Ran Wang

Xiao-Fan Li

Jia-Li Zeng

Pei-Xuan Lan

Hui-Xian Li

Bin Zhang

Chun Hu

Junyu Xu

Jian-Hong Luo

Affiliations

Soon will be listed here.

Abstract

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

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