Herber Charlotte S, Pratt Karishma J B, Shea Jeremy M, Villeda Saul A, Giocomo Lisa M
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
Nat Commun. 2025 Oct 3;16(1):8770. doi: 10.1038/s41467-025-63229-0.
Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged in vivo electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often, but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial coding quality. These genes were interneuron-enriched and related to synaptic plasticity, notably including a perineuronal net component. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.
在不同物种中，空间记忆会随着年龄的增长而衰退，这可能反映出海马体和内嗅皮质（MEC）功能的改变。然而，衰老的MEC中细胞和网络水平空间编码的完整性尚不清楚。在这里，我们利用体内电生理学来评估在虚拟环境中导航的年轻、中年和老年小鼠的MEC功能。在老年网格细胞中，我们观察到特定情境空间放电的稳定性受损，这与空间记忆缺陷相关。此外，老年网格网络经常改变放电模式，但与情境变化的对齐性较差。在不变的环境中，老年空间放电也不稳定。在这些相同的小鼠中，我们鉴定出458个在MEC中随年龄差异表达的基因，其中61个基因的表达与空间编码质量相关。这些基因在内侧神经元中富集，并且与突触可塑性相关，特别是包括一个神经元周围网络成分。总之，这些发现确定了MEC中与衰老过程中空间记忆受损相关的转录组、细胞和网络的协同变化。
