Hyper-Activation of mPFC Underlies Specific Traumatic Stress-Induced Sleep-Wake EEG Disturbances.

Tingting Lou,Zhiqiang Wang,Zhiyu Chen,Yuka Terakoshi,Qinghua Liu,Chia-Ying Lee,Liqin Cao,Greg Asher,Katsuyasu Sakurai,Jing Ma

doi:10.3389/fnins.2020.00883

Abstract

Sleep disturbances have been recognized as a core symptom of post-traumatic stress disorders (PTSD). However, the neural basis of PTSD-related sleep disturbances remains unclear. It has been challenging to establish the causality link between a specific brain region and traumatic stress-induced sleep abnormalities. Here, we found that single prolonged stress (SPS) could induce acute changes in sleep/wake duration as well as short- and long-term electroencephalogram (EEG) alterations in the isogenic mouse model. Moreover, the medial prefrontal cortex (mPFC) showed persistent high number of c-fos expressing neurons, of which more than 95% are excitatory neurons, during and immediately after SPS. Chemogenetic inhibition of the prelimbic region of mPFC during SPS could specifically reverse the SPS-induced acute suppression of delta power (1–4 Hz EEG) of non-rapid-eye-movement sleep (NREMS) as well as most of long-term EEG abnormalities. These findings suggest a causality link between hyper-activation of mPFC neurons and traumatic stress-induced specific sleep–wake EEG disturbances.

Highlights

Exposure to catastrophic traumatic events could lead to severe mental and behavioral disorders, so called post-traumatic stress disorders (PTSD), which are characterized by symptoms of reexperiencing, numbing, avoidance, and hyperarousal (Germain, 2013; Khazaie et al, 2016)
We used the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system to investigate whether hyper-activation of PrL neurons play an important role in traumatic stress-induced sleep–wake disturbances
All associated viruses (AAV)-injected mice were sequentially subjected to sleep deprived for 4 h (SD4) and single prolonged stress (SPS) treatments as described above (Figure 1), except for intraperitoneal injection of vehicle during SD4 or Clozapine N-oxide (CNO) during SPS at ZT0 and ZT3.5, and followed by continuous EEG/EMG recording for seven days (Figure 6A)

Summary

Introduction

Exposure to catastrophic traumatic events could lead to severe mental and behavioral disorders, so called post-traumatic stress disorders (PTSD), which are characterized by symptoms of reexperiencing, numbing, avoidance, and hyperarousal (Germain, 2013; Khazaie et al, 2016). There have been reports mPFC Underlies Stress-Induced Sleep Disturbances of increased (Woodward et al, 2000; Insana et al, 2012), decreased (Cohen et al, 2013), or no difference (Mellman et al, 2007) in the beta power of EEG during rapid-eye-movement sleep (REMS) in adult PTSD patients. These conflicting findings may be attributed to the effects of many confounding variables in the experimental settings, the inter-individual differences and disease heterogeneity, such as differences in initial traumatic stimuli, analysis stages of the illness, comorbidities with other psychiatric conditions, and diversity of underlying neural mechanisms (Kobayashi et al, 2007; Yetkin et al, 2010; Germain, 2013; Baglioni et al, 2016; Khazaie et al, 2016; Deslauriers et al, 2018)

Objectives

Methods

Results

Conclusion