Fan Yi, Tian Minjie, Chen Yan, Qi Xinyang, Zhang Qian, Yin Kuiying, Shi Jingping, Xiao Ming
Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
Mol Neurobiol. 2025 Apr 8. doi: 10.1007/s12035-025-04852-2.
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.
小脑 Crus II 与阿尔茨海默病（AD）的晚期有关，但其在记忆调节中的具体作用和治疗潜力仍不清楚。利用体内光纤光度法，我们观察到健康小鼠在识别记忆任务期间 Crus II 神经元的强烈激活。对 Crus II 神经元的急性化学遗传学抑制损害了小鼠的识别和空间记忆。多突触回路追踪显示，Crus II 神经元通过 Crus II-小脑外侧核（LN）-腹内侧丘脑/未定带（VM/ZI）-PrL 通路调节对侧前边缘皮层（PrL）的神经活动。在 5×FAD 小鼠中，Crus II 中的β-淀粉样蛋白（Aβ）斑块沉积呈现年龄依赖性进展，与前额叶皮层相比，发生时间较晚且程度较轻。对 Crus II 神经元的慢性激活改善了 5×FAD 小鼠的识别和空间记忆缺陷。这些发现突出了小脑 Crus II 作为认知功能的调节因子以及 AD 的潜在治疗靶点。
