Chronic antidepressant treatment rescues abnormally reduced REM sleep theta power in socially defeated rats

Yoshiki Matsuda,Naomi Nihonmatsu-Kikuchi,Yoshitaka Tatebayashi,Takiko Shinozaki,Kazuhisa Aoki,Toshikazu Shinba,Nobuyuki Ozawa

doi:10.1038/s41598-021-96094-0

Yoshiki Matsuda, Naomi Nihonmatsu-Kikuchi + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-96094-0

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Abstract

The effects of chronic antidepressant (AD) treatment on sleep disturbances in rodent chronic stress models have not been thoroughly investigated. Here, we show that chronic social defeat stress (SDS) in rats induces prolonged social avoidance, alterations in sleep architecture (increased total rapid eye movement [REM] sleep duration, bout, and shortened REM latency), and contextual but not cued fear memory deficits, even 1 month after the last SDS. These abnormalities were associated with changes in electroencephalography (EEG) spectral powers, including reduced REM sleep theta power during the light phase. Chronic treatment with two different classes of antidepressants (ADs), imipramine and fluoxetine, significantly ameliorated these behavioral, sleep, and EEG abnormalities. Interestingly, REM theta power was normalized by chronic (1 month) but not 1 week AD administration and solely correlated with the ratio (an objective indicator) of social interaction 1 month after the last SDS. These data suggest that reductions in REM sleep theta power, an EEG parameter that has never been directly investigated in humans, is a core sleep symptom in socially defeated rats, and, potentially, also in patients with stress-related psychiatric disorders, including major depressive and posttraumatic stress disorders.

Highlights

Psychological stressors generally have prominent effects on sleep, especially rapid eye movement (REM) sleep
We investigated the effects of chronic FLU or IMI treatment on these changes and found that, among several sleep disturbances rescued by ADs, decreased REM sleep theta power was a core sleep symptom associated with maladaptive social avoidance in rats
sleep deprivation (SD) rats exhibited near-complete social avoidance of the unfamiliar resident (BN) rats (Fig. 1e). This near-complete social avoidance was observed toward unfamiliar, nonaggressive SD littermates (Fig. 1f), suggesting that social avoidance was not an adaptive response to social defeat stress (SDS) and a maladaptive response[17,21]

Summary

Introduction

Psychological stressors generally have prominent effects on sleep, especially rapid eye movement (REM) sleep. Subjected to this psychological stress by sensory interactions with aggressors through clear, perforated dividers in shared home cages for the duration of the experiment (generally 10 days) This procedure has been shown to lead to the development of MDD- and anxiety-like behaviors in all C57BL/6J mice, only a subset of mice (called “susceptible” mice, defined by the presence of social avoidance against aggressive CD-1 mice18) exhibit maladaptive changes, including near-permanent social avoidance against nonaggressive C57BL6/J littermates[17,21], anhedonia, and metabolic s yndrome[18,22], all of which can be reversed by chronic but not acute administration of two different classes of ADs, fluoxetine (FLU) and imipramine (IMI)[17,21,23]. Limited information has been reported about long-term, post-stress effects

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