Graduate Program for Neuroscience, Department of Physiology and Biophysics, Boston University, Boston, United States.
Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
Elife. 2022 Jun 15;11:e72135. doi: 10.7554/eLife.72135.
In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. 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 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.
在衰老的大脑中，许多导致认知和行为能力下降的变化仍然不为人知。秀丽隐杆线虫提供了一个强大的衰老研究模型，其简单而经过充分研究的神经系统有助于我们进一步了解伴随衰老而来的细胞变化和功能改变。我们对衰老的线虫神经系统进行了多神经元功能成像，测量了与系统范围功能组织随年龄增长而出现的衰退相关的指标。在单细胞分辨率下，我们检测到活动动态向更高频率的转变。此外，我们还测量到一种特定的抑制性信号丢失，这种丢失发生在衰老过程的早期，并改变了系统的关键兴奋/抑制平衡。通过钙通道亚基 UNC-2/CaV2α的突变可以再现这些效应。我们发现，抑制性 GABA 信号的操纵可以部分改善或加速衰老的影响。胰岛素信号通路的破坏（已知可延长寿命）或半胱天冬酶激活的减少也部分减轻了衰老的影响。来自哺乳动物的数据与我们的发现一致，这表明随着年龄的增长，兴奋性/抑制性信号平衡发生了保守性转变，导致全局神经元动力学和功能下降的崩溃。
