A midbrain GABAergic circuit constrains wakefulness in a mouse model of stress.

Enhancement of wakefulness is a prerequisite for adaptive behaviors to cope with acute stress, but hyperarousal is associated with impaired behavioral performance. Although the neural circuitries promoting wakefulness in acute stress conditions have been extensively identified, less is known about the circuit mechanisms constraining wakefulness to prevent hyperarousal. Here, we found that chemogenetic or optogenetic activation of GAD2-positive GABAergic neurons in the midbrain dorsal raphe nucleus (DRNGAD2) decreased wakefulness, while inhibition or ablation of these neurons produced an increase in wakefulness along with hyperactivity. Surprisingly, DRNGAD2 neurons were paradoxically wakefulness-active and were further activated by acute stress. Bidirectional manipulations revealed that DRNGAD2 neurons constrained the increase of wakefulness and arousal level in a mouse model of stress. Circuit-specific investigations demonstrated that DRNGAD2 neurons constrained wakefulness via inhibition of the wakefulness-promoting paraventricular thalamus. Therefore, the present study identified a wakefulness-constraining role DRNGAD2 neurons in acute stress conditions.

The paraventricular thalamus is a critical thalamic area for wakefulness.

Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia. Moreover, our findings indicate that the PVT-nucleus accumbens projections and hypocretin neurons in the lateral hypothalamus to PVT glutamatergic neurons' projections are the effector pathways for wakefulness control. These results demonstrate that the PVT is a key wakefulness-controlling nucleus in the thalamus.

Response Inhibition Deficits in Insomnia Disorder: An Event-Related Potential Study With the Stop-Signal Task.

Background: Response inhibition is a hallmark of executive function, which was detected impaired in various psychiatric disorders. However, whether insomnia disorder (ID) impairs response inhibition has caused great controversy. Methods: Using the auditory stop-signal paradigm coupled with event-related potentials (ERPs), we carried out this study to examine whether individuals with ID presented response inhibition deficits and further investigated the neural mechanism correlated to these deficits. Twelve individuals with ID and 13 matched good sleepers (GSs) had participated in this study, and then they performed an auditory stop-signal task (SST) in the laboratory setting with high density EEG recordings. Results: The behavioral results revealed that compared to GSs, patients with ID presented significantly longer stop-signal reaction time (SSRT), suggesting the impairment of motor inhibition among insomniacs. Their reaction time in go trials, however, showed no significant between-group difference. Considering the electrophysiological correlate underlying the longer SSRT, we found reduced P3 amplitude in patients with insomnia in the successful stop trials, which might reflect their poor efficiency of response inhibition. Finally, when we performed exploratory analyses in the failed stop and go trials, patients with ID presented reduced Pe and N1 amplitude in the failed sop trials and go trials respectively. Discussion: Taken together, these findings indicate that individuals with ID would present response inhibition deficits. Moreover, the electrophysiological correlate underlying these deficits mainly revolves around the successful stop P3 component. The present study is the first to investigate the electrophysiological correlate underlying the impaired response inhibition among insomniacs.

Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition.

Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 µM, 300 µM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition.

Abnormal amplitude of low-frequency fluctuations associated with rapid-eye movement in chronic primary insomnia patients.

PURPOSE: Chronic primary insomnia (CPI) is the most prevalent sleep disorder worldwide. CPI manifests as difficulties in sleep onset, maintaining sleep, prolonged sleep latency, and daytime impairment and is often accompanied by cognitive problems such as poor academic performance, poor attention, and decreased memory. The most popular explanation of insomnia is hyperarousal or increased activities of neurons. Rapid eye movement (REM) sleep detected by polysomnography (PSG) exhibits a positive relationship with brain homeostasis and can be helpful for optimally preparing an organism for emotional and social function. Limited work has been performed to explore brain function of insomnia patients in combination with PSG analysis. RESULTS: We observed increased ALFF within areas related to hyperarousal such as the midbrain and bilateral extra-nucleus, whereas decreased ALFF was observed within areas associated with memory and attention involving the parietal and occipital lobule and others. Furthermore, the altered ALFF was associated with the duration of insomnia, sleep efficiency, duration of REM, latency of RME and ratio of REM. MATERIALS AND METHODS: In this study, we recruited twenty-five CPI patients and twenty-five normal sleep (NS) volunteers as a control group to investigate the amplitude of low-frequency fluctuations (ALFF) and the correlation between those altered ALFF regions through resting-state fMRI and PSG data. CONCLUSIONS: These findings suggest that hyperarousal reflected by ALFF abnormality within brain areas related to cognition and emotion in insomnia associated with REM sleep.

Efficacy of repetitive transcranial magnetic stimulation in the treatment of patients with chronic primary insomnia.

This study assessed the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of patients with chronic primary insomnia. Hundred and twenty patients with chronic primary insomnia were randomly assigned to three study groups (n = 40 per group): rTMS, medication, or psychotherapy treatment (both latter as controls). The treatments proceeded for 2 weeks, after which treatment efficacies were assessed in each study group based on changes in polysomnography parameters, Pittsburgh sleep quality index, and indices of HPA and HPT axes (serum cortisol, adrenocorticotropic hormone, highly sensitive thyrotropin, free T3, and free T4). Further, the relapse and recurrence rates within 3 months after respective treatments were also measured. rTMS treatment significantly better (p < 0.05) improved stage III sleep and REM sleep cycle compared with both control groups. Further, rTMS treatment group was more advantageous in improving the indices of HPA and HPT axes (p < 0.05 vs. both control groups). In addition, the relapse and recurrence rates were also the lowest in rTMS treatment group. In conclusion, rTMS treatment is more advantageous than both medication and psychotherapy treatments in improving the sleep architecture. Further, rTMS significantly decreases the body awakening level and provides a better long-term treatment effect.