Early-Stage Corticostriatal Circuit Hyperactivity Impairs Cholinergic Function and Cognitive Flexibility in an Alzheimer’s Model

作者：Yufei S. Huang, Xuan Xie, Zhenbo Huang, Ruifeng Chen, Himanshu Gangal, Xuehua Wang, Karienn Souza, Julia Hunter, Xin Wu, Doodipala Samba Reddy, Jeannie Chin, Jun Wang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.01.13.699380 · 被引用次数：2 · 研究领域：Alzheimer's disease research and treatments、Memory and Neural Mechanisms、Neuroscience and Neuropharmacology Research

Abstract Cognitive flexibility deficits are a hallmark of early-stage Alzheimer’s disease (AD), but the underlying circuit mechanisms remain poorly understood. Here, we show that the 5xFAD mouse model of AD neuropathology exhibited early deficits in instrumental reversal learning, indicating cognitive inflexibility preceding spatial memory deficits. This impairment was associated with excessive neuronal reactivation in the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS), key regions for goal-directed behavior. Electrophysiological recordings revealed that mPFC neurons in young 5xFAD mice were hyperexcitable and received elevated excitatory input. Moreover, the mPFC-to-direct pathway medium spiny neuron (dMSN) circuit and the dMSNs themselves were selectively hyperactive. These hyperactive dMSNs exerted increased inhibitory control over cholinergic interneurons (CINs) in the DMS, coinciding with reduced CIN firing and diminished striatal acetylcholine (ACh) release. Critically, sustained chemogenetic inhibition of the mPFC-to-DMS circuit in 5xFAD mice reduced cortical Aβ accumulation, normalized glutamatergic transmission in both the mPFC and DMS, restored striatal ACh levels, and rescued reversal learning deficits. Together, these findings identify a hyperactive mPFC-to-DMS circuit that disrupts corticostriatal and cholinergic signaling, contributing to cognitive inflexibility in 5xFAD mice. Targeting this circuit may offer a therapeutic strategy to preserve co...