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 hypera

SUBMITTER: Huang Y 

PROVIDER: S-EPMC12871269 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature