Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction in an Alzheimer’s Disease Model

Cognitive flexibility declines early in Alzheimer’s disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased excitatory input. Furthermore, glutamatergic transmission from the medial prefrontal cortex to striatal direct-pathway medium spiny neurons is enhanced and coincides with strengthened inhibitory transmission onto striatal cholinergic interneurons, reduced spontaneous firing, and diminished striatal acetylcholine release. Critically, sustained chemogenetic inhibition of this corticostriatal circuit attenuates cortical amyloid accumulation, reduces glutamatergic transmission, and increases acetylcholine levels. This also rescues reversal learning deficits in 5xFAD mice. Here, we show that pathological corticostriatal hyperactivity contributes to early cognitive inflexibility in a mouse model of Alzheimer’s disease.