Cellular and Molecular Mechanisms of REM Sleep Homeostatic Drive: A Plausible Component for Behavioral Plasticity.

Subimal Datta,Michael D Oliver

doi:10.3389/fncir.2017.00063

Abstract

Homeostatic regulation of REM sleep drive, as measured by an increase in the number of REM sleep transitions, plays a key role in neuronal and behavioral plasticity (i.e., learning and memory). Deficits in REM sleep homeostatic drive (RSHD) are implicated in the development of many neuropsychiatric disorders. Yet, the cellular and molecular mechanisms underlying this RSHD remain to be incomplete. To further our understanding of this mechanism, the current study was performed on freely moving rats to test a hypothesis that a positive interaction between extracellular-signal-regulated kinase 1 and 2 (ERK1/2) activity and brain-derived neurotrophic factor (BDNF) signaling in the pedunculopontine tegmentum (PPT) is a causal factor for the development of RSHD. Behavioral results of this study demonstrated that a short period (<90 min) of selective REM sleep restriction (RSR) exhibited a strong RSHD. Molecular analyses revealed that this increased RSHD increased phosphorylation and activation of ERK1/2 and BDNF expression in the PPT. Additionally, pharmacological results demonstrated that the application of the ERK1/2 activation inhibitor U0126 into the PPT prevented RSHD and suppressed BDNF expression in the PPT. These results, for the first time, suggest that the positive interaction between ERK1/2 and BDNF in the PPT is a casual factor for the development of RSHD. These findings provide a novel direction in understanding how RSHD-associated specific molecular changes can facilitate neuronal plasticity and memory processing.

Highlights

A significant body of research, exploring the inner workings of learning and memory, has suggested that the mechanisms regulating REM sleep homeostatic drive (RSHD) are critical for the development, maturation and plasticity of the brain (Garcia-Rill, 1991; Datta, 2000; Garcia-Rill et al, 2008; Shaffery et al, 2012a,b; Dumoulin Bridi et al, 2015; Frank, 2015; Kocsis, 2016)
In the vehicle control group of rats (VC + REM sleep control (RSC)), the microinjection recording session was comparable to the final baseline recording session in terms of time spent in REM sleep (11.0 ± 0.82% vs. 10.0 ± 0.56%) and number of REM sleep episodes (9.3 ± 0.76 vs. 7.8 ± 0.79)
The principal findings of this study are as follows: (1) homeostatic drive for REM sleep increased during short-term selective RSR; (2) during short-term RSR, brain-derived neurotrophic factor (BDNF) protein expression and extracellularsignal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and activation increased in the pedunculopontine tegmentum (PPT); (3) local application of the ERK1/2 activation inhibitor, U0126, into the PPT, inhibited ERK1/2 phosphorylation and activity; (4) local application of the ERK1/2 activation inhibitor into the PPT suppressed short-term selective RSR-induced increases in RSHD and BDNF expression; FIGURE 6 | Working model depicting molecular steps in the PPT cholinergic neurons involved in the regulation of RSHD

Summary

Introduction

A significant body of research, exploring the inner workings of learning and memory, has suggested that the mechanisms regulating REM sleep homeostatic drive (RSHD) are critical for the development, maturation and plasticity of the brain (Garcia-Rill, 1991; Datta, 2000; Garcia-Rill et al, 2008; Shaffery et al, 2012a,b; Dumoulin Bridi et al, 2015; Frank, 2015; Kocsis, 2016). Studies using a variety of training paradigms have shown that memory processing increases the homeostatic drive for sleep (Datta and O’Malley, 2013; Poe, 2017). Sleep homeostasis reflects a centrally mediated drive, which increases during sleep restriction and resolves during sleep recovery (Datta and Maclean, 2007; Datta et al, 2015). The mechanisms for homeostatic regulation of NR are well documented, the mechanisms underlying homeostatic regulation of REM sleep remain incomplete (Faraguna et al, 2008; Thakkar et al, 2008; Datta et al, 2015; Bjorness et al, 2016)

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