Spontaneous sleep–wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats

Abstract

SUMMARYBrain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation.

Sleep Deprivation and Gene Expression

“…The gene expression and protein levels of neurotrophic factors involved with cell growth and function (Boyd and Gordon 2003a, b) have also been shown to be affected by sleep deprivation (Cirelli and Tononi 2000a;Sei et al 2000;Fujihara et al 2003;Hamatake et al 2011;Ventskovska et al 2014;Wallingford et al 2014;Zielinski et al 2014). Most studies were concerned with BDNF, a neurotrophin of great importance for neuronal plasticity and survival (Ghosh et al 1994;Ventimiglia et al 1995;Lipsky and Marini 2007;Sossin and Barker 2007).…”

Concise Review: Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function

“…One route by which sleep deprivation could impact adult DG neurogenesis and thereby affect hippocampal function is through epigenetic modifications. Both acute and chronic sleep deprivation produce broad changes in epigenetic markers and patterns of gene transcription in rodents and humans . Of particular interest, depriving mice of sleep for 3 days downregulates hippocampal CBP expression, reduces hippocampal histone acetylation levels at Bdnf promoter regions, and weakens spatial memory , suggesting that sleep deprivation can impair cognition by disrupting hippocampal BDNF signaling, which is important for the maturation and growth of adult‐born DG neurons .…”

Activation of brain‐derived neurotrophic factor signaling in the basal forebrain reverses acute sleep deprivation‐induced fear memory impairments

“…Increase in BDNF protein level could be caused by enhanced expression and secretion, or reduced degradation of BDNF (Lessmann & Brigadski, 2009). After acute sleep deprivation, an exon‐specific increase in the expression of BDNF transcripts 1, 4, and 9a was found in the basal forebrain, while the 5‐methylcytosine DNA modification, which is important for the daily regulation of BDNF in the basal forebrain, was absent (Ventskovska, Porkka‐Heiskanen, & Karpova, 2015). Based on these results, the increased expression of BDNF might be attributed to increased transcription and translation.…”