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- Gregory S Wirak
- Jeremy Florman
- Mark J Alkema
- Christopher W Connor
- Christopher V Gabel
In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. C. 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, alongside a specific loss of inhibitory signaling occurring early in the aging process. These effects are partially delayed or accelerated by a long-lived or neurodegenerative mutant background, respectively. We further provide evidence that these effects are partially mediated through degradation of GABA signaling, via a pathway involving UNC-2/CaV2α and caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age leading to functional decline.