Treadmill exercise alters the single-nuclei and spatial transcriptional profiles of mouse aging across the neocortex and hippocampus

Aging drives a progressive decline in cognition that may be delayed by exercise (Ex). Neocortex (CTX) and hippocampus (HIP) are crucial brain regions for cognition but vulnerable to aging. Whether and how Ex induces changes in molecular and spatial signatures of aging across CTX and HIP remains little known. Herein, we assessed the effects of treadmill Ex against cognitive aging, and characterized the molecular and spatial changes by aging and upon Ex across the CTX and HIP at the single-nuclei resolution. Overall, Ex demonstrated cognitive benefits in old mice and largely protected the brain cells against aging, especially the neurons. Ex regulated the inhibitory neuron-specific aging-associated genes Alcam, Cacna2d3, and Foxp2, rebuilt the cellular communications and distance that were disrupted by aging, and reorganized the spatial distribution of cells across the aging brain, particularly the CTX, which may collectively contribute to the rejuvenation of cognitive function in aged mice. This study provides invaluable insights into Ex-induced benefits against cognitive aging. To explore the effects of Ex on brain aging, particularly cognitive aging, and to investigate whether and how Ex induces changes in molecular and spatial signatures of aging across CTX and HIP.衰老是认知能力进行性衰退的关键驱动因素，而运动（exercise, Ex）可延缓这一衰退进程。新皮层（Neocortex, CTX）与海马体（Hippocampus, HIP）是介导认知功能的关键脑区，同时也易受衰老的侵袭。目前学界对于运动是否能诱导新皮层与海马体中衰老相关的分子及空间特征改变，以及其具体作用机制仍知之甚少。本研究中，我们评估了跑步机运动对认知衰老的干预效应，并通过单细胞核分辨率（single-nuclei resolution）技术解析了新皮层与海马体中衰老及运动诱导的分子与空间特征变化。整体而言，运动可使老年小鼠获得认知益处，并在很大程度上抵御脑细胞的衰老损伤，对神经元的保护作用尤为突出。运动可靶向调控抑制性神经元特异性衰老相关基因Alcam、Cacna2d3与Foxp2的表达，重建了被衰老破坏的细胞通讯通路与细胞间空间距离，同时重构了衰老大脑内细胞的空间分布格局，尤其在新皮层区域；上述变化或可协同促进老年小鼠认知功能的年轻化修复。本研究为运动对抗认知衰老的有益作用提供了极具价值的研究见解。本研究旨在探究运动对脑衰老（尤其是认知衰老）的影响，并阐明运动是否能诱导新皮层与海马体中衰老相关的分子及空间特征改变，及其具体作用机制。