Reduced Sleep During Social Isolation Leads to Cellular Stress and Induction of the Unfolded Protein Response

Sleep. 2017 Jul 1;40(7):zsx095. doi: 10.1093/sleep/zsx095.

Abstract

Study objectives: Social isolation has a multitude of negative consequences on human health including the ability to endure challenges to the immune system, sleep amount and efficiency, and general morbidity and mortality. These adverse health outcomes are conserved in other social species. In the fruit fly Drosophila melanogaster, social isolation leads to increased aggression, impaired memory, and reduced amounts of daytime sleep. There is a correlation between molecules affected by social isolation and those implicated in sleep in Drosophila. We previously demonstrated that acute sleep loss in flies and mice induced the unfolded protein response (UPR), an adaptive signaling pathway. One mechanism indicating UPR upregulation is elevated levels of the endoplasmic reticular chaperone BiP/GRP78. We previously showed that BiP overexpression in Drosophila led to increased sleep rebound. Increased rebound sleep has also been demonstrated in socially isolated (SI) flies.

Methods: D. melanogaster were used to study the effect of social isolation on cellular stress.

Results: SI flies displayed an increase in UPR markers; there were higher BiP levels, increased phosphorylation of the translation initiation factor eIF2α, and increased splicing of xbp1. These are all indicators of UPR activation. In addition, the effects of isolation on the UPR were reversible; pharmacologically and genetically altering sleep in the flies modulated the UPR.

Conclusions: The reduction in sleep observed in SI flies is a cellular stressor that results in UPR induction.

Keywords: Drosophila; cellular stress; sleep; social isolation; unfolded protein response (UPR).

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Eukaryotic Initiation Factor-2 / metabolism
  • Female
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Male
  • Phosphorylation
  • RNA Splicing
  • Signal Transduction
  • Sleep / drug effects
  • Sleep / genetics
  • Sleep / physiology*
  • Social Isolation*
  • Stress, Physiological*
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / genetics
  • Unfolded Protein Response / physiology*
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • Eukaryotic Initiation Factor-2
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Xbp1 protein, Drosophila