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. 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/CaV2a. 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.
All data generated or analyzed during this study are included in the manuscript and supporting files.
- Christopher W Connor
- Christopher V Gabel
- Jeremy Florman
- Mark J Alkema
- Gregory S Wirak
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Manuel Zimmer, University of Vienna, Austria
© 2022, Wirak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Naturally occurring body movements and collective neural activity both exhibit complex dynamics, often with scale-free, fractal spatiotemporal structure. Scale-free dynamics of both brain and behavior are important because each is associated with functional benefits to the organism. Despite their similarities, scale-free brain activity and scale-free behavior have been studied separately, without a unified explanation. Here we show that scale-free dynamics of mouse behavior and neurons in visual cortex are strongly related. Surprisingly, the scale-free neural activity is limited to specific subsets of neurons, and these scale-free subsets exhibit stochastic winner-take-all competition with other neural subsets. This observation is inconsistent with prevailing theories of scale-free dynamics in neural systems, which stem from the criticality hypothesis. We develop a computational model which incorporates known cell-type-specific circuit structure, explaining our findings with a new type of critical dynamics. Our results establish neural underpinnings of scale-free behavior and clear behavioral relevance of scale-free neural activity.
Information from the sensory periphery is conveyed to the cortex via structured projection pathways that spatially segregate stimulus features, providing a robust and efficient encoding strategy. Beyond sensory encoding, this prominent anatomical feature extends throughout the neocortex. However, the extent to which it influences cortical processing is unclear. In this study, we combine cortical circuit modeling with network theory to demonstrate that the sharpness of topographic projections acts as a bifurcation parameter, controlling the macroscopic dynamics and representational precision across a modular network. By shifting the balance of excitation and inhibition, topographic modularity gradually increases task performance and improves the signal-to-noise ratio across the system. We demonstrate that in biologically constrained networks, such a denoising behavior is contingent on recurrent inhibition. We show that this is a robust and generic structural feature that enables a broad range of behaviorally-relevant operating regimes, and provide an in-depth theoretical analysis unravelling the dynamical principles underlying the mechanism.