Ugidos I F, Iglesias J C, Milanes S, Farahani F, Mostany R
bioRxiv. 2025 Sep 7:2025.09.02.673642. doi: 10.1101/2025.09.02.673642.
Healthy aging is accompanied by a gradual decline in higher-order cognitive functions, including working memory, attention, and cognitive flexibility, processes that critically rely on intact frontal cortical circuits. While neuronal loss is minimal during aging, whether there are changes in functional plasticity in this region remains unexplored. In this regard, dendritic spines, the primary postsynaptic structures of excitatory synapses, act as key hubs for experience-dependent synaptic remodeling. Using longitudinal two-photon imaging in Thy1-eGFP-M mice, we examined age-related changes in dendritic spine density and dynamics in layer 5 pyramidal neurons of the secondary motor area (MOs), a frontal cortical region essential for strategy switching and cognitive flexibility, and that was assessed using an operant conditioning paradigm. We found that aged mice (18-22 months) exhibited significant impairments in cognitive flexibility relative to young mice (3-5 months) in the four-odor choice discrimination and reversal task. Analysis of dendritic spine plasticity revealed that baseline spine density, turnover, and morphology were largely preserved in aged mice. Sex differences were evident, with females displaying higher spine density and a greater fraction of stable spines, a feature maintained across aging. Importantly, despite preserved baseline architecture, aged mice showed impaired ketamine-induced spinogenesis and reduced stabilization of newly formed spines, in contrast to the robust structural plasticity observed in young mice. These results indicate that healthy aging selectively impairs activity-dependent synaptic remodeling without affecting steady-state spine architecture in frontal cortical circuits. By linking deficits in induced synaptic plasticity to age-related impairments in cognitive flexibility, our study highlights the critical need to target plasticity mechanisms as a therapeutic strategy to restore executive function and cognitive adaptability in the aging brain.
健康衰老伴随着高阶认知功能的逐渐衰退，包括工作记忆、注意力和认知灵活性，这些过程严重依赖于完整的额叶皮质回路。虽然衰老过程中神经元损失极少，但该区域功能可塑性是否发生变化仍未得到探索。在这方面，树突棘作为兴奋性突触的主要突触后结构，是经验依赖性突触重塑的关键枢纽。我们利用Thy1-eGFP-M小鼠进行纵向双光子成像，研究了次级运动区（MOs）第5层锥体神经元树突棘密度和动力学的年龄相关变化，MOs是额叶皮质区域，对策略转换和认知灵活性至关重要，并使用操作性条件反射范式对其进行评估。我们发现，在四气味选择辨别和反转任务中，老年小鼠（18-22个月）相对于年轻小鼠（3-5个月）在认知灵活性方面表现出显著损伤。对树突棘可塑性的分析表明，老年小鼠的基线棘密度、周转率和形态在很大程度上得以保留。性别差异明显，雌性小鼠的棘密度更高，稳定棘的比例更大，这一特征在衰老过程中保持不变。重要的是，尽管基线结构得以保留，但与年轻小鼠中观察到的强大结构可塑性相反，老年小鼠的氯胺酮诱导的棘生成受损，新形成棘的稳定性降低。这些结果表明，健康衰老选择性地损害了活动依赖性突触重塑，而不影响额叶皮质回路中的稳态棘结构。通过将诱导突触可塑性的缺陷与年龄相关的认知灵活性损伤联系起来，我们的研究强调了将可塑性机制作为恢复衰老大脑执行功能和认知适应性的治疗策略的迫切需求。
