Cerebellar Crus II Regulates Recognition and Spatial Memory in Mice.

The cerebellar Crus II is implicated in the late stages of Alzheimer's disease (AD), yet its specific roles in memory regulation and therapeutic potential remain unclear. Using in vivo fiber photometry, we observed robust activation of Crus II neurons in healthy mice during recognition memory tasks. Acute chemogenetic inhibition of Crus II neurons impaired recognition and spatial memory in mice. Polysynaptic circuit tracing revealed that Crus II neurons modulate neural activity in the contralateral prelimbic cortex (PrL) via the Crus II-cerebellar lateral nucleus (LN)-ventromedial thalamus/zona incerta (VM/ZI)-PrL pathway. In 5 × FAD mice, β-amyloid (Aβ) plaque deposition in Crus II exhibited age-dependent progression, occurring later and less severely compared to the prefrontal cortex. Chronic activation of Crus II neurons ameliorated recognition and spatial memory deficits in 5 × FAD mice. These findings highlight the cerebellar Crus II as a modulator of cognitive function and a potential therapeutic target for AD.