Decrease In Rapid Eye Movement Sleep Research Articles

Exploring the Evolution of Sleep Patterns From Infancy to Adolescence.

Sleep is a critical component of healthy development, particularly during the formative years from infancy through adolescence. Sleep undergoes continuous change throughout life characterized by frequent awakenings and a high proportion of rapid eye movement (REM) sleep during infancy, changes in sleep architecture, an increase in non-rapid eye movement (NREM) sleep during adolescence, and an eventual decrease in REM sleep in old age. Adequate sleep is therefore essential for cognitive development, especially between ages 10 and 16. Sleep deprivation may negatively affect academic performance, attention regulation, and emotional well-being. Biological factors, such as hormonal changes during puberty, significantly influence sleep patterns, leading to later bedtimes and a tendency for chronic sleep deprivation in adolescents. Environmental factors, including light exposure and screen time, also play a critical role in regulating sleep. This paper examines the evolution of sleep patterns across infancy and adolescence, describing changes in sleep architecture, timing, and regulation. The influence of biological, environmental, and socio-cultural factors on sleep is explored, highlighting how these factors collectively shape sleep behaviors and health outcomes. It also addresses the profound role sleep plays in cognitive development, brain maturation, and emotional well-being. The importance of understanding sleep patterns and their developmental trajectories to address sleep-related issues is emphasized. Promoting healthy sleep from an early age can enhance cognitive and emotional outcomes, contributing to better academic performance and overall well-being in children and adolescents. The findings advocate for further standardized sleep intervention programs globally to prioritize sleep health and support optimal development.

Altered sleep architecture following consecutive nights of presleep alcohol.

Alcohol consumption before sleep decreases sleep latency, explaining the common use of alcohol as a sleep aid. The full impact of alcohol on sleep architecture is not well understood, particularly the potential cumulative effects of presleep alcohol consumption across consecutive nights. Here, we describe the effects of presleep alcohol on sleep architecture across three consecutive nights. Thirty adult participants took part in a crossover, within-participants study consisting of two sets of three consecutive nights of in-lab polysomnography. For each series of nights, participants drank one of the two beverages: a mixer only or a mixer plus alcohol (targeting a BrAC of 0.08 mg/L), ending 1 hour before lights out. Polysomnography (PSG) was used to stage sleep, and standard sleep variables were extracted. Linear mixed-effect analysis and generalized additive modeling were used to examine the effect of alcohol on sleep architecture. Alcohol before sleep increased the rate of slow wave sleep (SWS) accumulation across all three nights and decreased the rate of rapid eye movement (REM) sleep accumulation at the start of each night. Alcohol also decreased the total amount of REM sleep but did not affect the total amount of SWS each night. These data indicate that drinking alcohol before sleep substantially affects sleep architecture, including changes to the rate of accumulation of SWS and REM sleep. We show that alcohol disrupts normal sleep architecture, leading to a significant decrease in REM sleep; thus, the use of alcohol as a sleep aid remains a public health concern.

Effect of prolonged sedation with dexmedetomidine, midazolam, propofol, and sevoflurane on sleep homeostasis in rats

BackgroundSleep disruption is a common occurrence during medical care and is detrimental to patient recovery. Long-term sedation in the critical care setting is a modifiable factor that affects sleep, but the impact of different sedative–hypnotics on sleep homeostasis is not clear. MethodsWe conducted a systematic comparison of the effects of prolonged sedation (8 h) with i.v. and inhalational agents on sleep homeostasis. Adult Sprague–Dawley rats (n=10) received dexmedetomidine or midazolam on separate days. Another group (n=9) received propofol or sevoflurane on separate days. A third group (n=12) received coadministration of dexmedetomidine and sevoflurane. Wakefulness (wake), slow-wave sleep (SWS), and rapid eye movement (REM) sleep were quantified during the 48-h post-sedation period, during which we also assessed wake-associated neural dynamics using two electroencephalographic measures: theta-high gamma phase-amplitude coupling and high gamma weighted phase-lag index. ResultsDexmedetomidine-, midazolam-, or propofol-induced sedation increased wake and decreased SWS and REM sleep (P<0.0001) during the 48-h post-sedation period. Sevoflurane produced no change in SWS, decreased wake for 3 h, and increased REM sleep for 6 h (P<0.02) post-sedation. Coadministration of dexmedetomidine and sevoflurane induced no change in wake (P>0.05), increased SWS for 3 h, and decreased REM sleep for 9 h (P<0.02) post-sedation. Dexmedetomidine, midazolam, and coadministration of dexmedetomidine with sevoflurane reduced wake-associated phase-amplitude coupling (P≤0.01). All sedatives except sevoflurane decreased wake-associated high gamma weighted phase-lag index (P<0.01). ConclusionsIn contrast to i.v. drugs, prolonged sevoflurane sedation produced minimal changes in sleep homeostasis and neural dynamics. Further studies are warranted to assess inhalational agents for long-term sedation and sleep homeostasis.

0353 Effect of Lemborexant on Sleep Architecture in Adult and Elderly Subjects with Mild to Severe Obstructive Sleep Apnea

Abstract Introduction Lemborexant (LEM) is a dual-orexin-receptor antagonist approved to treat adults with insomnia. In such patients, LEM increased total sleep, with prominent increases in rapid eye movement (REM). Since patients with obstructive sleep apnea (OSA) may report sleep difficulties and show decreased REM sleep, sleep architecture was analyzed after treatment with LEM. Methods Studies 102 and 113 were double-blind, placebo (PBO)-controlled crossover studies in adult and elderly subjects with mild (apnea-hypopnea index [AHI] ≥5 to &amp;lt; 15) or moderate (AHI ≥15 to &amp;lt; 30)/severe (AHI ≥30) OSA, respectively, without insomnia. Subjects were randomized to LEM 10mg (LEM10) or PBO in two 8-night treatment periods (separated by ≥14 days). Least-squares-mean (LSM) for each sleep stage (minutes) was compared across conditions on Days 1 (D1) and 8 (D8). Treatment-emergent adverse events (TEAEs) were recorded. Results The analysis set comprised 39 subjects with mild OSA and 33 with moderate/severe OSA. On both days, total sleep time was significantly higher in the LEM condition in subjects with mild (D1: LEM10, 434.08; PBO, 385.46; P&amp;lt; 0.0001; D8: LEM10, 415.90; PBO, 386.85; P=0.003) and moderate/severe (D1: LEM10, 423.10; PBO, 385.48; P&amp;lt; 0.0001; D8: LEM10, 416.96; PBO, 385.57; P=0.001) OSA. Compared with PBO, total non-REM sleep significantly increased only on D1 in subjects with mild OSA (D1: LEM10, 330.57; PBO, 308.55; P=0.001; D8: LEM10, 323.77; PBO, 308.97; P=0.060) but on both days in subjects with moderate/severe OSA (D1: LEM10, 343.23; PBO, 327.45; P=0.006; D8: LEM10, 341.83; PBO, 322.48; P=0.018). Total REM sleep significantly increased in subjects with mild (D1: LEM10, 103.59; PBO, 76.91; P&amp;lt; 0.0001; D8: LEM10, 92.13; PBO, 77.93; P=0.004) and moderate/severe (D1: LEM10, 79.87; PBO, 58.03; P&amp;lt; 0.0001; D8: LEM10, 75.13; PBO, 62.69; P=0.006) OSA. REM latency was significantly decreased on both days in subjects with mild OSA (D1: LEM10, 51.96; PBO, 83.36; P&amp;lt; 0.0001; Day 8: LEM10, 67.52; PBO, 102.34; P=0.005) and only on D1 in subjects with moderate/severe OSA (D1: LEM10, 72.13; PBO, 98.90; P=0.029; D8: LEM10, 90.42; PBO, 106.63; P=0.242). LEM was well-tolerated; most TEAEs were mild. Conclusion In OSA subjects without insomnia, LEM nevertheless increased total sleep, non-REM, and REM sleep versus PBO. Support (if any) Eisai Inc.

Gut Microbiota Composition and Functionality Are Associated With REM Sleep Duration and Continuous Glucose Levels.

Sleep disruption is associated with worse glucose metabolic control and altered gut microbiota in animal models. We aimed to evaluate the possible links among rapid eye movement (REM) sleep duration, continuous glucose levels, and gut microbiota composition. This observational, prospective, real-life, cross-sectional case-control study included 118 (60 with obesity), middle-aged (39.1-54.8 years) healthy volunteers recruited at a tertiary hospital. Glucose variability and REM sleep duration were assessed by 10-day continuous glucose monitoring (CGM) (Dexcom G6) and wrist actigraphy (Fitbit Charge 3), respectively. The coefficient of variation (CV), interquartile range (IQR), and SD of glucose variability was assessed and the percentage of time in range (% TIR), at 126-139 mg/dL (TIR2), and 140-199 mg/dL (TIR3) were calculated. Shotgun metagenomics sequencing was applied to study gut microbiota taxonomy and functionality. Increased glycemic variability (SD, CV, and IQR) was observed among subjects with obesity in parallel to increased % TIR2 and % TIR3. REM sleep duration was independently associated with % TIR3 (β = -.339; P < .001) and glucose variability (SD, β = -.350; P < .001). Microbial taxa from the Christensenellaceae family (Firmicutes phylum) were positively associated with REM sleep and negatively with CGM levels, while bacteria from Enterobacteriacea family and bacterial functions involved in iron metabolism showed opposite associations. Decreased REM sleep duration was independently associated with a worse glucose profile. The associations of species from Christensenellaceae and Enterobacteriaceae families with REM sleep duration and continuous glucose values suggest an integrated picture of metabolic health.

Reduction in the propensity of rapid eye movement sleep and phasic-to-tonic ratio in patients with refractory epilepsy.

Patients with epilepsy exhibit disturbed sleep architecture and shorter rapid eye movement (REM) sleep compared with healthy controls. REM sleep consists of two microstates, phasic and tonic REM. Studies suggest that epileptic activity is suppressed in phasic but not in tonic REM. However, changes in the REM microstructure in patients with epilepsy are still unknown. Therefore, this study evaluated the differences in REM microstructure between patients with refractory and medically controlled epilepsy. This retrospective case-control study included patients with refractory and medically controlled epilepsy. Sleep parameters of the patients were recorded by standard polysomnography. In addition, the microstructures of sleep and REM sleep were compared between the two epilepsy groups. Forty-two patients with refractory epilepsy and 106 with medically controlled epilepsy were evaluated. The refractory group showed significantly decreased REM sleep (p = 0.0062), particularly in the first and second sleep cycles (p = 0.0028 and 0.00482, respectively), as well as longer REM latency (p = 0.0056). Eighteen and 28 subjects in the refractory and medically controlled epilepsy groups, respectively, with comparable REM sleep percentages, underwent REM microstructure examination. Phasic REM sleep was significantly lower in the refractory group (4.5% ± 2.1% vs. 8.0% ± 4.1%; p = 0.002). In addition, the phasic-to-tonic ratio was significantly decreased (4.8 ± 2.3 vs. 8.9 ± 4.9; p = 0.002) and negatively associated with refractory epilepsy (coefficient = -0.308, p = 0.0079). Patients with refractory epilepsy exhibited REM sleep disturbance at both macro and microstructure levels.

Motor neuron involvement threatens survival in spinocerebellar ataxia type 1.

Motor neuron involvement threatens survival in spinocerebellar ataxia type 1.

Sleep alterations are related to cognitive symptoms in Parkinson's disease: A 24-hour ambulatory polygraphic EEG study

BackgroundSleep disorders are frequent and early non-motor symptoms of Parkinson's disease (PD). As a consequence of histopathological changes, the regulation of rapid eye movement (REM) sleep is affected in PD causing REM sleep behaviour disorder in about half of the patients. Considering the well-known role of sleep in memory formation processes, our aim was to investigate the relationship between sleep alterations and cognitive performance to elucidate the possible association between sleep, and especially REM sleep changes and cognitive dysfunction in PD. MethodsWe investigated 25 PD patients and 20 healthy controls. All participants underwent a 24-hour-long 19-channel polygraphic EEG recording, neurological, neuroimaging and neuropsychological examination. The visually analysed sleep-EEG and neuropsychological data were statistically evaluated. ResultsThe intergroup analysis showed significant decrease of REM and N3, but increase of N2 sleep ratio, and significantly lower scores in the verbal fluency in PD compared to healthy controls. While we found significant negative correlation between verbal fluency and REM-sleep in the whole sample, we observed a marginal significant correlation between phonemic fluency and REM sleep in the PD group. ConclusionThe negative correlation between verbal fluency performance and REM sleep duration suggests the role of decreased REM sleep in cognitive dysfunction in PD. The early involvement of REM sleep regulation with parallel executive dysfunction in PD emphasise the important role of REM sleep deterioration in the neurodegenerative process of PD.

Sleep-wake disturbances in supra-and infratentorial stroke: an analysis of post-acute sleep architecture and apnea

Background and purposeSleep-wake disturbances (SWD) are common following stroke, and often extend into the post-acute to chronic periods of recovery. Of particular interest to recovery is a reduction in rapid eye movement (REM) sleep, as we know REM sleep to be important for learning and memory. While there is a breadth of evidence linking SWD and stroke, much less work has been done to identify and determine if differences in sleep architecture and apnea severity are dependent on stroke infarct topographies. MethodsA retrospective chart review was conducted of 48 ischemic stroke patients having underwent a full, overnight polysomnography (PSG). All patients were over 30 days post-injury (post-acute) at the time of the PSG. Patients were divided into supra- and infratentorial infarct topography groups based on available medical and imaging records. In addition to sleep study record review, cognitive and outcome measures were examined. ResultsResults showed that patients with infratentorial stroke had poorer sleep efficiency, decreased REM sleep, and higher apnea hypopnea index (AHI) than those with supratentorial injuries. Longer continuous REM periods were correlated with higher verbal learning/memory scores, higher levels of positive affect, and lower levels of emotional/behavioral dyscontrol. Neither age nor AHI were significantly correlated with the amount or duration of REM. Slow-wave sleep was significantly reduced across both injury topographies. ConclusionsInfratentorial ischemic stroke patients display significant disruptions in sleep architecture and may require close monitoring for SWDs in the post-acute period to maximize outcome potential. REM sleep is particularly affected when compared to supratentorial ischemic stroke.

Quantitative evaluation of the microstructure of rapid eye movement sleep in refractory epilepsy: a preliminary study using electroencephalography and heart rate variability analysis

IntroductionPatients with epilepsy have a disturbed sleep architecture. Polysomnographic studies have shown that patients with refractory epilepsy have decreased rapid eye movement (REM) sleep and longer REM latency than those with medically controlled epilepsy. However, little is known about the differences in the REM sleep microstructure between these patient groups. MethodsWe conducted a retrospective case–control study of 20 patients with refractory epilepsy (refractory group) and 28 patients with medically controlled epilepsy (medically controlled group). All patients completed sleep questionnaires and underwent overnight in-lab polysomnography. Five-minute electroencephalogram recordings at the C3 and C4 electrodes from each REM sleep were selected for spectral analysis, and 5-min electrocardiogram segments recorded during REM sleep were used for heart rate variability analysis. The groups’ scores on the sleep questionnaires, polysomnographic sleep parameters, indices of sleep-related breathing disorders, and REM sleep electroencephalogram spectra were compared. ResultsThe refractory group had decreased REM sleep (p < 0.001) and longer REM latency (p = 0.0357) than those of the medically controlled group. Moreover, electroencephalogram spectral analysis revealed that the refractory group had decreased absolute beta power (p = 0.0039) and relative beta power (p = 0.0035) as well as increased relative delta power (p = 0.0015) compared with the medically controlled group. ConclusionsDifferences in the polysomnographic macrostructure and REM sleep microstructure between the study groups suggest REM sleep dysregulation in patients with refractory epilepsy.

The Defensive Activation Theory: REM Sleep as a Mechanism to Prevent Takeover of the Visual Cortex.

Regions of the brain maintain their territory with continuous activity: if activity slows or stops (e.g., because of blindness), the territory tends to be taken over by its neighbors. A surprise in recent years has been the speed of takeover, which is measurable within an hour. These findings lead us to a new hypothesis on the origin of REM sleep. We hypothesize that the circuitry underlying REM sleep serves to amplify the visual system’s activity periodically throughout the night, allowing it to defend its territory against takeover from other senses. We find that measures of plasticity across 25 species of primates correlate positively with the proportion of rapid eye movement (REM) sleep. We further find that plasticity and REM sleep increase in lockstep with evolutionary recency to humans. Finally, our hypothesis is consistent with the decrease in REM sleep and parallel decrease in neuroplasticity with aging.

Fentanyl and Morphine Cause Dose‐Dependent Sleep Disruption in C57BL/6J (B6) Mice

Opioids are important for pain management but have the unwanted side effect of sleep disruption in humans (Sleep Med Clin 13:271, 2018), rats (Sci Rep 9:14122, 2019), and mice (Neurosci Abstr Online 502.02, 2019). Dose-response data are needed for efforts to develop countermeasures to the undesired effects of opioids. Therefore, this study is testing the hypothesis that the sleep-disrupting effects of opioids are dose dependent. Experiments were conducted in accordance with the FASEB Statement of Principles for the use of Animals in Research and Education. Adult male B6 mice (n=8) were housed in a temperature- and humidity-controlled environment and 12:12h light:dark cycle. Mice were implanted with telemeters (DSI HD-X02) to record cortical electroencephalogram (EEG) and neck muscle electromyogram. These measures made it possible to objectively quantify the effects of opioids on states of wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. One week after recovery from surgery, each mouse began receiving subcutaneous injections (0.3 mL) within 60 min of light onset. States of sleep and wakefulness were recorded for 4 h after each injection. Repeated injections into the same mouse were separated by 3 or 4 days. Saline (vehicle control) was followed by increasing, half log doses (mg/kg) of morphine (0.01 to 30) or fentanyl (0.001 to 3). Every 10 s of each 4-h recording was scored by two individuals, one of whom was blinded to the treatment condition. Sleep scoring concordance between the scorers was >90%. Data were analyzed using repeated measures ANOVA and Tukey's multiple comparisons test (GraphPad Prism V9). Morphine (F(8, 56) = 104.4, p <0.0001) and fentanyl (F(8, 56) = 94.65, p < 0.0001) dose-dependently increased wakefulness, decreased NREM sleep (F(8, 56) = 110.2, p <0.0001; F(8, 56) = 96.30, p < 0.0001) and decreased REM sleep (F(8, 56) = 34.00, p <0.0001; F(8, 56)= 51.80, p <0.0001). The lowest dose of morphine that significantly increased wakefulness and decreased NREM sleep was 1 mg/kg (p = 0.04, p = 0.03); and 3 mg/kg for decreasing REM sleep (p = 0.0004). For fentanyl, the lowest dose that significantly increased wakefulness and decreased NREM and REM sleep was 0.3 mg/kg (p = 0.001; p = 0.0016; p = 0.0007). Higher doses of morphine and fentanyl eliminated NREM and REM sleep. Both opioids also significantly and differentially altered EEG power during wakefulness (see companion abstract by O’Brien et al.). Nonlinear regression was used to calculate the half-maximal dose (mg/kg) for increasing wakefulness (ED50) and inhibiting sleep (ID50). ED50 and ID50 data were used to compare drug potency. Morphine ED50 was 2.2 to increase wakefulness, ID50 2.3 to decrease NREM sleep, and 1.3 to decrease REM sleep. Fentanyl ED50 was 0.2 to increase wakefulness, ID50 0.2 to decrease NREM sleep, and 0.1 to decrease REM sleep. These data demonstrate that opioid-induced sleep disruption is dose-dependent, and that fentanyl is more potent than morphine to disrupt sleep.

Manipulation of rapid eye movement sleep via orexin and GABAA receptor modulators differentially affects fear extinction in mice: effect of stable versus disrupted circadian rhythm.

Sleep disruption, and especially rapid eye movement (REM) sleep disruption, is associated with fear inhibition impairment in animals and humans. The REM sleep-fear inhibition relationship raises concern for individuals with posttraumatic stress disorder (PTSD), whose sleep disturbance is commonly treated with hypnotics that disrupt and/or decrease REM sleep, such as benzodiazepines or "Z-drugs." Here, we examined the effects of the Z-drug zolpidem, a gamma-aminobutyric acidA (GABAA) receptor positive allosteric modulator, as well as suvorexant, an orexin receptor antagonist (hypnotics which decrease and increase REM sleep, respectively) in the context of circadian disruption in murine models of fear inhibition-related processes (i.e. fear extinction and safety learning). Adult male C57Bl/6J mice completed fear and safety conditioning before undergoing shifts in the light-dark (LD) cycle or maintaining a consistent LD schedule. Fear extinction and recall of conditioned safety were thereafter tested daily. Immediately prior to the onset of the light phase between testing sessions, mice were treated with zolpidem, suvorexant, or vehicle (methylcellulose). Polysomnographic analyses showed the temporal distribution of REM sleep was misaligned during LD cycle-shifts, while REM sleep duration was preserved. Suvorexant increased REM sleep and improved fear extinction rate, relative to zolpidem, which decreased REM sleep. Survival analysis demonstrated LD shifted mice treated with suvorexant were faster to achieve complete extinction than vehicle and zolpidem-treated mice in the LD shifted condition. By contrast, retention of conditioned safety memory was not influenced by either treatment. This study thus provides preclinical evidence for the potential clinical utility of hypnotics which increase REM sleep for fear extinction after PTSD-relevant sleep disturbance.

The impact of antiseizure medications on polysomnographic parameters: a systematic review and meta-analysis

BackgroundOral antiseizure medications (ASMs) are first-line treatments for patients with epilepsy. However, ASMs may alter sleep architecture, adversely affecting patient outcomes. The meta-analysis aimed to elucidate the effect of ASMs on sleep architecture. MethodsPubMed, Embase, and Cochrane Central database (up to Febrary 2021) were searched for randomized control trials (RCT) with effects of ASMs on polysomnography parameters. A meta-analysis using a random-effects model was performed. We did not set limitation to the participants with underlying diagnosis of epilepsy. ResultsEighteen randomized-controlled trials fulfilled the eligibility criteria. The effects of five main groups of ASMs (sodium channel blockers, calcium channel blockers, GABA enhancers, synaptic vesicle glycoprotein 2A [SV2A] ligand, and broad-spetrum ASMs) on slow-wave sleep (SWS), rapid eye movement (REM) sleep, and sleep efficiency (SE) were analyzed. Compared with placebo, calcium channel blockers and GABA enhancers significantly increased SWS. GABA enhancers also decreased REM sleep percentage, whereas calcium channel blockers significantly increased SE. Sodium channel blockers, SV2A ligand and broad-spectrum ASMs did not affect SWS, REM sleep, or SE. The subgroup analysis revealed that gabapentin, pregabalin, and tiagabine increased the percentage of SWS. Tiagabine also decreased REM sleep, whereas pregabalin increased SE. Finally, levetiracetam did not affect SWS, REM sleep, and SE. ConclusionsThis meta-analysis indicated that ASMs can have a statistically significant effect on sleep parameters; the effect differs between ASMs.

0575 Sleep Monitoring with a Single Channel EEG Recorder in Patients with Psychiatric Disorders

Abstract Introduction The gold standard of sleep measurement has been laboratory polysomnography (PSG). However, electrodes and cables can cause discomfort, and exposure to an unfamiliar environment can cause the “first-night effect.” Difficulty falling asleep or maintaining sleep, poor sleep quality, and nightmares are some of the key clinical symptoms observed among individuals with psychiatric disorders. Those suffering from sleep disorders often present with symptoms of discontent with regard to sleep quality, timing, and quantity, and these symptoms have an adverse impact on function and quality of life. A minimally invasive technique would be preferable in patients with psychiatric disorders, who tend to be sensitive to environmental change. Accordingly, we evaluated the performance of a single-channel electroencephalography (EEG)-based sleep monitoring system in patients with psychiatric disorders. Methods Fifty-nine patients undergoing PSG were enrolled in this study. Single-channel EEG sleep monitoring was performed simultaneously with PSG. PSG and the EEG recordings were used to evaluate sleep parameters, such as total sleep time (TST), sleep efficiency, rapid eye movement (REM) sleep, light sleep (stages N1 and N2), and deep sleep (stage N3). Correlation analysis was used to evaluate the agreement on sleep parameters and attributing factors to the inaccuracies of the single-channel EEG recording. Results TST, sleep efficiency, REM sleep duration, and non-REM sleep duration of the single-channel EEG-based sleep monitoring showed a significant correlation with those of PSG. Lower sleep efficiency, a decrease in REM sleep, and increases in waking after sleep onset, arousal index, and apnea/hypopnea index were associated with the difference of sleep parameters between the two methods. Conclusion Among patients with psychiatric disorders who are sensitive to environmental change single-channel EEG sleep monitoring would be a useful technique to objectively evaluate sleep quality. Support Collaboration study with The KAITEKI Institute, Inc.

Activation of Preoptic GABAergic or Glutamatergic Neurons Modulates Sleep-Wake Architecture, but Not Anesthetic State Transitions.

The precise mechanism of general anesthesia remains unclear. In the last two decades, there has been considerable focus on the hypothesis that anesthetics co-opt the neural mechanisms regulating sleep. This hypothesis is supported by ample correlative evidence at the level of sleep-promoting nuclei, but causal investigations of potent inhaled anesthetics have not been conducted. Here, we tested the hypothesis that chemogenetic activation of discrete neuronal subpopulations within the median preoptic nucleus (MnPO) and ventrolateral preoptic nucleus (VLPO) of the hypothalamus would modulate sleep/wake states and alter the time to loss and resumption of consciousness associated with isoflurane, a potent halogenated ether in common clinical use. We show that activating MnPO/VLPO GABAergic or glutamatergic neurons does not alter anesthetic induction or recovery time. However, activation of these neuronal subpopulations did alter sleep-wake architecture. Notably, we report the novel finding that stimulation of VLPO glutamatergic neurons causes a strong increase in wakefulness. We conclude that activation of preoptic GABAergic or glutamatergic neurons that increase sleep or wakefulness does not substantively influence anesthetic state transitions. These data indicate that the correlative evidence for a mechanistic overlap of sleep and anesthesia at the level of an individual nucleus might not necessarily have strong causal significance.

Hypocretin in median raphe nucleus modulates footshock stimuli-induced REM sleep alteration

Stress is one of major factors that cause sleep problems. Hypocretin represents a stress-related neuropeptide and is well known in maintaining physiological wakefulness. The hypocretinergic neurons originate in the lateral hypothalamic area (LHA) and transmit to several brain regions, including the median raphe nuclei (MRNs). The MRNs modulate both fear responses and sleep-wake activity; however, it remains unclear whether stress alters the levels of hypocretin to regulate MRNs and consequently disrupt sleep. In this paper, we employed the inescapable footshock stimuli (IFS) as a stressor and hypothesized that the IFS-induced sleep disruption is mediated by increased hypocretins in the MRNs. Our results demonstrate that the concentrations of hypocretin in the hypothalamus increased after IFS. Rapid eye movement (REM) sleep was reduced after footshock, and microinjection of non-selective hypocretin receptor antagonist TCS-1102 into the MRNs blocked the IFS-induced decrease of REM sleep. Furthermore, administration of hypocretins into the MRNs mimicked the IFS-induced REM sleep reduction. These results conclude that the increased levels of hypocretins in the MRNs mediate the IFS-induced REM sleep reduction.

MON-471 A New Look at the Endocrinology of Posttraumatic Stress Disorder (PTSD)

Background Typically, individuals with PTSD have: [a] decreased rapid eye movement (REM) sleep, [b] low cortisol (F) response to ACTH after dexamethasone suppression (dex-ACTH) despite elevated ACTH levels, and [c] are often hypertensive. However, there has been no comprehensive understanding of the underlying endocrinology of PTSD. Without REM sleep, PTSD patients would be expected to be GH deficient, but this has yet to be confirmed. Children in severely stressed environments, perhaps equivalent to PTSD, have decreased REM sleep, poor growth and a low GH response to testing. Children with isolated GH deficiency have a decreased F response to dex-ACTH, but their corticosterone (B) response to dex-ACTH is exaggerated. Treatment with exogenous hGH for 3 days stimulates 17-hydroxylase and restores the normal F to B ratio after dex-ACTH. B measurements after dex-ACTH have not been made in patients with PTSD. We have recently reported the discovery of Ionotropin. Ionotropin shares a structural element (a 5-membered lactone ring) with spironolactone. Ionotropin seems to function as an endogenous equivalent. High levels of Ionotropin are frequently observed in patients with hypertension. New synthesis The lack of REM sleep suggests that many patients with PTSD are functionally GH deficient. This would restrict 17-hydroxylase activity and lead to increased B and decreased F. Both B and F are glucocorticoids. However, B is a potent mineralocorticoid but F much less so. Mineralocorticoids, such as B, stimulate the Na+ channel, leading to Na+ retention and K+ wasting. To compensate for the K+ wasting, a patient would synthesize Ionotropin, which would cause hypertension. K+ wasting (including hypokalemia) is known to be associated with mental problems. One example is Bartter's syndrome. Affected patients benefit from therapy with triamterene or amiloride. New approaches to therapy Evaluate REM sleep and confirm low IGF levels. Choose drugs known to improve REM sleep, rather than anti-depressants. Confirm elevated B to F ratios, either episodically or after ACTH administration. Test if a short course of hGH or IGF1 therapy restores normal B to F ratios. Amiloride and triamterene are K+ sparing diuretics and block synthesis of the Na+ channel, which is a key part of the response to mineralocorticoids. This therapy could reduce K+ wasting, reducing Ionotropin synthesis, and lead to lower blood pressures. Strict low Na+ diets might also be helpful. Monitoring IGF and/or Ionotropin levels might be useful markers to evaluate new therapies. Notes This hypothesis does not imply that all patients with PTSD have this trilogy. There may be multiple diseases that present with the PTSD psychiatric phenotype. As women with pre-eclampsia have high levels of a digoxin-like material, which might be Ionotropin, this might be the explanation why pregnant women with PTSD are at increased risk of developing pre-eclampsia.

Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep.

The pathophysiological function of the G-protein coupled melatonin MT1 and MT2 receptors has not yet been well-clarified. Recent advancements using selective MT1/ MT2 receptor ligands and MT1/MT2 receptor knockout mice have suggested that the activation of the MT1 receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT1 knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT1 receptors is also distinct from MT2 receptors; for example, MT2 receptors are located in the reticular thalamus (NREM area), while the MT1 receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT1-MT2 receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT1/MT2 non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT1 and MT2 receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT2 agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT1 agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT1 but not MT2 receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT1 and/or MT2 receptors as targets for neuropsychopharmacology drug development.

Ablation of Central Serotonergic Neurons Decreased REM Sleep and Attenuated Arousal Response.

Sleep/wake behavior is regulated by distinct groups of neurons, such as dopaminergic, noradrenergic, and orexinergic neurons. Although monoaminergic neurons are usually considered to be wake-promoting, the role of serotonergic neurons in sleep/wake behavior remains inconclusive because of the effect of serotonin (5-HT)-deficiency on brain development and the compensation for inborn 5-HT deficiency by other sleep/wake-regulating neurons. Here, we performed selective ablation of central 5-HT neurons in the newly developed Rosa-diphtheria toxin receptor (DTR)-tdTomato mouse line that was crossed with Pet1Cre/+ mice to examine the role of 5-HT neurons in the sleep/wake behavior of adult mice. Intracerebroventricular administration of diphtheria toxin completely ablated tdTomato-positive cells in Pet1Cre/+; Rosa-DTR-tdTomato mice. Electroencephalogram/electromyogram-based sleep/wake analysis demonstrated that central 5-HT neuron ablation in adult mice decreased the time spent in rapid eye movement (REM) sleep, which was associated with fewer transitions from non-REM (NREM) sleep to REM sleep than in control mice. Central 5-HT neuron-ablated mice showed attenuated wake response to a novel environment and increased theta power during wakefulness compared to control mice. The current findings indicated that adult 5-HT neurons work to support wakefulness and regulate REM sleep time through a biased transition from NREM sleep to REM sleep.