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Comparative single-cell RNA sequencing brain atlas of larval Astyanax mexicanus surface and Pachón cavefish

ABSTRACT: Transcriptional changes underlie not only adaptations of animals to novel or changing environments, but also to human disease phenotypes, such as insomnia. Linking specific transcriptional variations to observable traits can reveal the genetic basis of adaptive trait evolution and disease. To link genetic variation to phenotypic differences, we constructed the first single nucleus RNA sequencing (snRNA seq) brain atlas in a uniquely suited model system, the Mexican tetra Astyanax mexicanus. We made comparisons between surface and cavefish A. mexicanus morphs, which despite having dramatically different life histories, physiologies, and morphologies, can nevertheless interbreed. Here we show a suite of genetic changes that underlie specific differences in phenotypes, including synaptic and neural rewiring, as well as circadian dysregulation between surface and cave-dwelling morphs that may underlie human sleep disorders. Our comprehensive snRNA seq brain atlas revealed widespread divergence in the abundance and molecular signatures of neurons and glia between surface and cavefish and establishes a platform for uncovering the genetic underpinnings of cavefish disease phenotypes.

ORGANISM(S): Astyanax mexicanus

PROVIDER: GSE328673 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Dysregulation of sleep has widespread health consequences and represents an enormous health burden. Short-sleeping individuals are predisposed to the effects of neurodegeneration, suggesting a critical role for sleep in the maintenance of neuronal health. While the effects of sleep on cellular function are not completely understood, growing evidence has identified an association between sleep loss and DNA damage, raising the possibility that sleep facilitates efficient DNA repair. The Mexican tetra fish,Astyanax mexicanusprovides a model to investigate the evolutionary basis for changes in sleep and the consequences of sleep loss. Multiple cave-adapted populations of these fish have evolved to sleep for substantially less time compared to surface populations of the same species without identifiable impacts on healthspan or longevity. To investigate whether the evolved sleep loss is associated with DNA damage and cellular stress, we compared the DNA Damage Response (DDR) and oxidative stress levels betweenA. mexicanuspopulations. We measured markers of chronic sleep loss and discovered elevated levels of the DNA damage marker γH2AX in the brain, and increased oxidative stress in the gut of cavefish, consistent with chronic sleep deprivation. Notably, we found that acute UV-induced DNA damage elicited an increase in sleep in surface fish but not in cavefish. On a transcriptional level, only the surface fish activated the photoreactivation repair pathway following UV damage. These findings suggest a reduction of the DDR in cavefish compared to surface fish that coincides with elevated DNA damage in cavefish. To examine DDR pathways at a cellular level, we created an embryonic fibroblast cell line from the two populations ofA. mexicanus. We observed that both the DDR and DNA repair were diminished in the cavefish cells, corroborating thein vivofindings and suggesting that the acute response to DNA damage is lost in cavefish. To investigate the long-term impact of these changes, we compared the transcriptome in the brain and gut of aged surface fish and cavefish. Strikingly, many genes that are differentially expressed between young and old surface fish do not transcriptionally vary by age in cavefish. Taken together, these findings suggest that have developed resilience to sleep loss, despite possessing cellular hallmarks of chronic sleep deprivation.

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Comparative single-cell RNA sequencing brain atlas of larval Astyanax mexicanus surface and Pachón cavefish

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