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

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 cognitive function in the early stages of AD. Highlights 5xFAD mice exhibit early cognitive deficits in instrumental reversal learning. mPFC neurons and corticostriatal circuits are hyperactive, while cholinergic neurons are hypoactive in 5xFAD mice. Sustained inhibition of mPFC-to-DMS circuit hyperactivity normalizes glutamatergic transmission and slows Aβ accumulation in 5xFAD mice. Sustained inhibition of the mPFC-to-DMS circuit rescues reversal learning deficits in 5xFAD mice.