Chronic antidepressant treatments rescue reduced REM sleep theta power in a rat social defeat stress model of depression

Abstract

Although It is widely recognized that virtually all antidepressants (ADs) suppress rapid eye movement (REM) sleep, the effects of chronic AD treatments on sleep abnormalities, especially those of REM sleep, have rarely been investigated comprehensively in animal models of major depressive disorder (MDD). Here, we show that chronic social defeat stress (SDS) in rats induces prolonged social avoidance and MDD-like alterations in sleep architecture (increased REM sleep durations, bouts, and shortened REM latency) even a month after the last SDS. These abnormalities were associated with changes in electroencephalography (EEG) spectra powers, such as reduced REM sleep theta powers during the light phase. Chronic AD treatments significantly ameliorated these behavioral, sleep, and EEG abnormalities, although in some cases not to control levels. Interestingly, the social interaction ratios a month after the last SDS most strongly correlated with the REM sleep theta powers. These results suggest that chronic AD treatments suppress REM sleep durations and bouts as observed in human MDD patients, but, at the same time, increase REM sleep theta power. The latter is an EEG parameter that has never been directly investigated in humans, and which may be responsible for the therapeutic effects of ADs.3 Significance StatementDisturbed sleep is one of nine diagnostic criteria for major depressive disorder (MDD), which usually resolves with adequate treatment. However, little is known about how antidepressants (AD) work in MDD animal models. Here, we developed a novel rat social defeat stress model demonstrating long-lasting MDD-like sleep disturbances. We found that chronic AD treatments suppressed REM durations and bouts as reported previously, but, at the same time, increased REM sleep theta power. Interestingly, among several sleep parameters, only REM sleep theta power strongly correlated with depressive symptoms at 1M. Thus, REM sleep theta power, an EEG parameter that has never been investigated directly in humans, could be a novel indicator for MDD and/or AD effects.

Ergothioneine, a metabolite of the gut bacteriumLactobacillus reuteri, protects against stress-induced sleep disturbances

“…This is partly because of the lack of knowledge regarding the CNS center responsible for disturbed sleep associated with MDD, a major behavioral phenotype recapitulated in the current model. Nonetheless, we focused on the septohippocampal pathways that generate the hippocampal REM theta oscillation [66], since REM theta powers most significantly correlated with the MDD-like social interactions in our SDS rats treated with antidepressants [3] and L-ergothioneine (Supplementary Fig. 3).…”

“…We applied a modified repeated SDS model [3] for 14 consecutive days using male Sprague Dawley (SD) rats that were approximately 8 weeks old (Charles River Laboratories Japan, Yokohama, Japan) at stress onset. Briefly, each SD rat was transferred into the home cage of a retired aggressive male Brown Norway (BN) rat (>7 months of age; Charles River Laboratories Japan).…”

“…In particular, the observed sleep abnormalities exhibit numerous similarities to those in patients with MDD. These include significantly increased rapid eye movement (REM) and decreased non-REM (NREM) sleep durations, increased sleep fragmentation, and decreased REM sleep latency during the light phase [3].…”

“…In addition to the core symptoms (depressed mood and loss of interest/pleasure), MDD can also be characterized by somatic symptoms such as sleep abnormalities [2]. We have recently developed a depression rat model using the 14day social defeat stress (SDS) paradigm [3]. Compared to other rodent stress models, nearly all SDS rats exhibit long-term social avoidance and MDD-like sleep abnormalities in our paradigm, which can be rescued by chronic antidepressant treatments [3].…”

“…We have recently developed a depression rat model using the 14day social defeat stress (SDS) paradigm [3]. Compared to other rodent stress models, nearly all SDS rats exhibit long-term social avoidance and MDD-like sleep abnormalities in our paradigm, which can be rescued by chronic antidepressant treatments [3]. In particular, the observed sleep abnormalities exhibit numerous similarities to those in patients with MDD.…”