Clock genes and behavioral responses to light are altered in a mouse model of diabetic retinopathy

PLoS One. 2014 Jul 9;9(7):e101584. doi: 10.1371/journal.pone.0101584. eCollection 2014.

Abstract

There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Clocks
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Retinopathy / genetics*
  • Diabetic Retinopathy / metabolism
  • Gene Expression
  • Light
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / radiation effects
  • Opsins / genetics
  • Opsins / metabolism
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism
  • Photoperiod
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Retina / metabolism
  • Retina / radiation effects
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / radiation effects
  • Transcriptional Activation / radiation effects*

Substances

  • Opsins
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Proto-Oncogene Proteins c-fos

Grant support

This research was supported by Rhône-Alpes CMIRA, GDRI-Neuro (CNRST/INSERM/CNRS), CNRST-INSERM PA/RN/2013, ARC Handicap Vieillissement Neurosciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.