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bioRxiv · 10.1101/2022.01.31.478444

Stress resilience is established during development and is regulated by complement factors

Swaminathan, A.·Gliksberg, M.·Anbalagan, S.·Wigoda, N.·Levkowitz, G.
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Abstract

Individuals in a population respond differently to stressful situations. While resilient individuals recover efficiently, others are susceptible to the same stressors. However, it remains challenging to identify resilience in mammalian embryos to determine if stress resilience is established as a trait during development or acquired later in life. Using a new behavioural paradigm in zebrafish larvae, we show that resilience is a trait that is determined and exhibited early in life. Resilient and susceptible individuals retained these traits throughout life and passed them on to the next generation. Resilient larvae showed higher expression of resilience-associated genes and larvae lacking neuropeptide Y and miR218 were significantly under-represented in the resilient population. Unbiased transcriptome analysis revealed that multiple factors of the innate immune complement cascade were downregulated in resilient larvae in response to stressors. Pharmacological inhibition and genetic knockouts of critical complement factors led to an increase in resilience. We conclude that resilience is established early during development as a stable trait, and that neuropeptides and the complement pathway play positive and negative roles in determining resilience respectively. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/478444v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@359261org.highwire.dtl.DTLVardef@11d1e62org.highwire.dtl.DTLVardef@b5d346org.highwire.dtl.DTLVardef@141bae1_HPS_FORMAT_FIGEXP M_FIG C_FIG Why some individual individuals recover better than others from stressful situations is unclear. We show that resilience to stress is established during zebrafish development as a stable and heritable trait. Resilience is augmented by brain-derived neuropeptides and attenuated by innate immune complement factors specifically expressed in the liver. HighlightsO_LIWildtype zebrafish larvae show differences in their dynamics of recovering from stress, with some being more resilient than others. C_LIO_LIResilience is a stable and heritable trait. C_LIO_LIResilient fish show specific stress-responsive transcriptional changes. C_LIO_LINeuropeptide Y and miRNA218 positively affect resilience, while innate immune complement factors attenuate resilience. C_LI

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Swaminathan, A., Gliksberg, M., Anbalagan, S., Wigoda, N., Levkowitz, G.. 2022-01-31. Stress resilience is established during development and is regulated by complement factors. https://doi.org/10.1101/2022.01.31.478444

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