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.衰老会引发认知能力的进行性衰退，而运动（exercise，缩写Ex）可延缓这一进程。新皮层（Neocortex，缩写CTX）与海马体（hippocampus，缩写HIP）是支撑认知功能的关键脑区，却极易受到衰老的侵袭。目前尚不清楚运动是否能够诱导新皮层与海马体产生衰老相关的分子及空间特征改变，且其具体调控机制也尚未明确。本研究借助单细胞核分辨率技术，评估了跑台运动对小鼠认知衰老的改善作用，并解析了衰老状态与运动干预下，新皮层与海马体的分子及空间特征变化。整体而言，跑台运动为老年小鼠带来了明确的认知益处，并可在很大程度上保护脑细胞免受衰老侵袭，尤以神经元为甚。运动可调控抑制性神经元特异性的衰老相关基因Alcam、Cacna2d3与Foxp2，修复衰老所破坏的细胞通讯网络与空间距离，并重塑衰老大脑（尤其是新皮层）内的细胞空间分布，上述效应或共同助力老年小鼠实现认知功能的年轻化。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科学见解。本研究旨在探究运动对脑衰老（尤其是认知衰老）的调控效应，并解析运动是否、以及如何诱导新皮层与海马体产生衰老相关的分子及空间特征改变。