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

Description

Yufei Huang and a large team report, in a 2026 mouse study, that an overactive brain circuit dulls mental flexibility early in Alzheimer's disease, before memory fails. Young mice bred to model the disease struggled to reverse an action for reward, even while spatial memory still held. Brain recordings showed reactivation in two linked areas, the medial prefrontal cortex and a striatal zone, and cortex neurons there fired too easily with excitatory input.

Signals from cortex to one striatal cell class ran stronger. A second class of striatal cells, which release the chemical acetylcholine, was more strongly hushed, fired less, and released less of its chemical. Quieting of the circuit with engineered switches lowered amyloid build-up in cortex, eased the excess signaling, and restored acetylcholine levels. The authors name early circuit overactivity, not cell loss alone, as a driver worth targeting while treatment can preserve thinking.

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Source: https://europepmc.org/article/MED/PMC13462761