Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in C. elegans
Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in C. elegans
复制标题
与年龄相关的神经元动力学变化涉及线虫抑制信号传导的丧失
DOI：
10.1101/2021.07.07.451497
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Gregory S Wirak, Jeremy Florman
中科院分区：
文献类型：
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作者：
Gregory S Wirak, Jeremy Florman
在衰老的大脑中，许多认知和行为衰退的潜在变化仍然不透明。秀丽隐杆线虫为衰老研究提供了一个强大的模型，它具有一个简单的、经过充分研究的神经系统，以进一步了解伴随衰老的细胞修饰和功能改变。我们对老年人进行多神经元功能成像。elegans神经系统，测量全系统功能组织中与年龄相关的故障。在单细胞分辨率下，我们检测到活动动态向更高频率的变化。此外，我们测量了在衰老过程早期发生的抑制信号的特定损失，并改变了系统的关键兴奋/抑制平衡。这些作用通过钙通道亚基CaV-2/CaV 2 α的突变来重现。我们发现，抑制GABA信号的操纵可以部分改善或加速老化的影响。衰老的影响也部分减轻了破坏胰岛素信号通路，已知增加寿命，或通过减少半胱天冬酶激活。来自哺乳动物的数据与我们的研究结果一致，表明兴奋/抑制信号的平衡随着年龄的增长而发生保守的变化，导致全局神经元动力学和功能下降。
In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. Caenorhabditis elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies. In addition, we measure a specific loss of inhibitory signaling that occurs early in the aging process and alters the systems’ critical excitatory/inhibitory balance. These effects are recapitulated with mutation of the calcium channel subunit UNC-2/CaV2α. We find that manipulation of inhibitory GABA signaling can partially ameliorate or accelerate the effects of aging. The effects of aging are also partially mitigated by disruption of the insulin signaling pathway, known to increase longevity, or by a reduction of caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age that leads to breakdown in global neuronal dynamics and functional decline.