"Count on Sleep": an OSA awareness project update.

Obstructive sleep apnea (OSA) is a common, chronic sleep-related breathing disorder that affects approximately 12% of the US adult population. Greater public awareness of OSA is necessary to decrease the number of people with undiagnosed or untreated OSA and reduce the negative health consequences of unrecognized OSA. In 2021, the American Academy of Sleep Medicine initiated the "Count on Sleep" project in partnership with key stakeholders with the objective of raising the awareness of OSA among the public, health care providers, and public health officials. Four workgroups implemented strategies and completed tasks focused on increasing OSA awareness in their targeted areas to address the objectives of the project including (1) Public Awareness and Communications, (2) Provider Education, (3) Tool Development and Surveillance, and (4) a Strategic Planning workgroup that coordinated efforts across the project. Over the first 2 years, workgroups made substantial progress toward project goals including holding "listening sessions" with representatives of communities disproportionately affected by OSA and its consequences, developing resources for primary care providers that can be easily accessed and used in practice, and developing a brief survey for use in estimating and tracking OSA risk across the population. Over the first 2 project years, workgroups made significant progress in advancing efforts to increase awareness of OSA in US communities. The third year of the project will focus on dissemination of campaign materials and resources for all targeted groups, including the public, health care professionals, and public health professionals. CITATION: Martin JL, Rowley J, Goel N, et al. "Count on Sleep": an OSA awareness project update. J Clin Sleep Med. 2024;20(2):303-307.

The Negative Effects of Travel on Student Athletes Through Sleep and Circadian Disruption.

Collegiate athletes must satisfy the academic obligations common to all undergraduates, but they have the additional structural and social stressors of extensive practice time, competition schedules, and frequent travel away from their home campus. Clearly such stressors can have negative impacts on both their academic and athletic performances as well as on their health. These concerns are made more acute by recent proposals and decisions to reorganize major collegiate athletic conferences. These rearrangements will require more multi-day travel that interferes with the academic work and personal schedules of athletes. Of particular concern is additional east-west travel that results in circadian rhythm disruptions commonly called jet lag that contribute to the loss of amount as well as quality of sleep. Circadian misalignment and sleep deprivation and/or sleep disturbances have profound effects on physical and mental health and performance. We, as concerned scientists and physicians with relevant expertise, developed this white paper to raise awareness of these challenges to the wellbeing of our student-athletes and their co-travelers. We also offer practical steps to mitigate the negative consequences of collegiate travel schedules. We discuss the importance of bedtime protocols, the availability of early afternoon naps, and adherence to scheduled lighting exposure protocols before, during, and after travel, with support from wearables and apps. We call upon departments of athletics to engage with sleep and circadian experts to advise and help design tailored implementation of these mitigating practices that could contribute to the current and long-term health and wellbeing of their students and their staff members.

Behavioral and Neuronal Characterizations, across Ages, of the TgSwDI Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects as many as 50 million people worldwide. It is neurochemically characterized by an aggregation of ß-amyloid plaques and tau neurofibrillary tangles that result in neuronal dysfunction, cognitive decline, and a progressive loss of brain function. TgSwDI is a well-studied transgenic mouse model of AD, but no longitudinal studies have been performed to characterize cognitive deficits or ß-amyloid plaque accumulation for use as a baseline reference in future research. Thus, we use behavioral tests (T-Maze, Novel Object Recognition (NOR), Novel Object Location (NOL)) to study long-term and working memory, and immunostaining to study ß-amyloid plaque deposits, as well as brain size, in hippocampal, cerebellum, and cortical slices in TgSwDI and wild-type (WT) mice at 3, 5, 8, and 12 months old. The behavioral results show that TgSwDI mice exhibit deficits in their long-term spatial memory starting at 8 months old and in long-term recognition memory at all ages, but no deficits in their working memory. Immunohistochemistry showed an exponential increase in ß-amyloid plaque in the hippocampus and cortex of TgSwDI mice over time, whereas there was no significant accumulation of plaque in WT mice at any age. Staining showed a smaller hippocampus and cerebellum starting at 8 months old for the TgSwDI compared to WT mice. Our data show how TgSwDI mice differ from WT mice in their baseline levels of cognitive function and ß-amyloid plaque load throughout their lives.

Reversible Suppression of Fear Memory Recall by Transient Circadian Arrhythmia.

We tested the hypothesis that a temporary period of circadian arrhythmia would transiently impair recall of an aversive memory in Siberian hamsters (Phodopus sungorus). Unlike mice or rats, circadian arrhythmia is easily induced in this species by a one-time manipulation of their ambient lighting [i.e., the disruptive phase shift (DPS) protocol]. Hamsters were conditioned to associate footshocks with a shock chamber (context) and with a predictive auditory tone (cue), and then exposed to the DPS protocol. Following DPS, animals either became arrhythmic (ARR), reentrained to the light-dark cycle (ENT), or became arrhythmic for < 14 days before their circadian locomotor rhythms spontaneously recovered and reentrained (ARR-ENT). Tests for contextual memory showed that freezing was decreased 9-10 days post-DPS when both ARR and ARR-ENT groups were arrhythmic. Once ARR-ENT animals reentrained (day 41), however, freezing was elevated back to Pre-DPS levels and did not differ from those observed in ENT hamsters. ENT animals maintained high levels of freezing at both time points, whereas, freezing remained low in ARR hamsters. In contrast to contextual responses, cued responses were unaffected by circadian arrhythmia; all three groups exhibited elevated levels of freezing in response to the tones. The differential impact of circadian arrhythmia on contextual versus cued associative memory suggests that arrhythmia preferentially impacts memory processes that depend on the hippocampus.

Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.

Aging disrupts circadian gene regulation and function in macrophages.

Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.

Question what is "known".

•We can "know" good data as true, but we cannot accept as fact interpretations of those data.•Example: the assumption that both NREM and REM sleep are functional responses to prior wake,•And, their cycling is controlled by a fixed period oscillator.•Further research shows NREM and REM sleep are in a homeostatic relationship.•Questioning interpretations can lead to valuable new research.

Disruption of circadian timing increases synaptic inhibition and reduces cholinergic responsiveness in the dentate gyrus.

We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters (Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long-term potentiation. However, dentate granule cells from circadian-arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian-intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 µM), and did so by increasing their membrane potential three-fold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus-evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus-evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate-CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian-arrhythmic hamsters.

Loss of Circadian Timing Disrupts Theta Episodes during Object Exploration.

This study examined whether theta oscillations were compromised by the type of circadian disruption that impairs hippocampal-dependent memory processes. In prior studies on Siberian hamsters, we developed a one-time light treatment that eliminated circadian timing in the central pacemaker, the suprachiasmatic nucleus (SCN). These arrhythmic animals had impaired hippocampal-dependent memory whereas animals made arrhythmic with SCN lesions did not. The current study examined whether theta oscillations are compromised by the same light treatment that produced memory impairments in these animals. We found that both methods of inducing circadian-arrhythmia shortened theta episodes in the EEG by nearly 50%. SCN-lesioned animals, however, exhibited a 3-fold increase in the number of theta episodes and more than doubled the total time that theta dominated the EEG compared to SCN-intact circadian-arrhythmic animals. Video tracking showed that changes in theta were paralleled by similar changes in exploration behavior. These results suggest that the circadian-arrhythmic SCN interferes with hippocampal memory encoding by fragmenting theta oscillations. SCN-lesioned animals can, however, compensate for the shortened theta episodes by increasing their frequency. Implications for rhythm coherence and theta sequence models of memory formation are discussed.

Suprachiasmatic lesions restore object recognition in down syndrome model mice.

The Ts65Dn mouse is a well-studied model of trisomy 21, Down syndrome. This mouse strain has severe learning disability as measured by several rodent learning tests that depend on hippocampal spatial memory function. Hippocampal long-term potentiation (LTP) is deficient in these mice. Short-term daily treatment with low-dose GABA receptor antagonists rescue spatial learning and LTP in Ts65Dn mice leading to the hypothesis that the learning disability is due to GABAergic over-inhibition of hippocampal circuits. The fact that the GABA receptor antagonists were only effective if delivered during the daily light phase suggested that the source of the excess GABA was controlled directly or indirectly by the circadian system. The central circadian pacemaker of mammals is the suprachiasmatic nucleus (SCN), which is largely a GABAergic nucleus. In this study we investigated whether elimination of the SCN in Ts65Dn mice would restore their ability to form recognition memories as tested by the novel object recognition (NOR) task. Full, but not partial lesions of the SCN of Ts65Dn mice normalized their ability to perform on the NOR test. These results suggest that the circadian system modulates neuroplasticity over the time frame involved in the process of consolidation of recognition memories.

The Function(s) of Sleep.

Sleep is a highly conserved phenomenon in endotherms, and therefore it must serve at least one basic function across this wide range of species. What that function is remains one of the biggest mysteries in neurobiology. By using the word neurobiology, we do not mean to exclude possible non-neural functions of sleep, but it is difficult to imagine why the brain must be taken offline if the basic function of sleep did not involve the nervous system. In this chapter we discuss several current hypotheses about sleep function. We divide these hypotheses into two categories: ones that propose higher-order cognitive functions and ones that focus on housekeeping or restorative processes. We also pose four aspects of sleep that any successful functional hypothesis has to account for: why do the properties of sleep change across the life span? Why and how is sleep homeostatically regulated? Why must the brain be taken offline to accomplish the proposed function? And, why are there two radically different stages of sleep?The higher-order cognitive function hypotheses we discuss are essential mechanisms of learning and memory and synaptic plasticity. These are not mutually exclusive hypotheses. Each focuses on specific mechanistic aspects of sleep, and higher-order cognitive processes are likely to involve components of all of these mechanisms. The restorative hypotheses are maintenance of brain energy metabolism, macromolecular biosynthesis, and removal of metabolic waste. Although these three hypotheses seem more different than those related to higher cognitive function, they may each contribute important components to a basic sleep function. Any sleep function will involve specific gene expression and macromolecular biosynthesis, and as we explain there may be important connections between brain energy metabolism and the need to remove metabolic wastes.A deeper understanding of sleep functions in endotherms will enable us to answer whether or not rest behaviors in species other than endotherms are homologous with mammalian and avian sleep. Currently comparisons across the animal kingdom depend on superficial and phenomenological features of rest states and sleep, but investigations of sleep functions would provide more insight into the evolutionary relationships between EEG-defined sleep in endotherms and rest states in ectotherms.

Functional Interactions Between Sleep and Circadian Rhythms in Learning and Learning Disabilities.

The propensity for sleep is timed by the circadian system. Many studies have shown that learning and memory performance is affected by circadian phase. And, of course it is well established that critical processes of memory consolidation occur during and depend on sleep. This chapter presents evidence that sleep and circadian rhythms do not just have separate influences on learning and memory that happen to coincide because of the circadian timing of sleep, but rather sleep and circadian systems have a critical functional interaction in the processes of memory consolidation. The evidence comes primarily from research on two models of learning disability: Down's syndrome model mice and Siberian hamsters. The Down's syndrome model mouse (Ts65Dn) has severe learning disability that has been shown to be due to GABAergic over-inhibition. Short-term, chronic therapies with GABAA antagonists restore learning ability in these mice long-term, but only if the antagonist treatments are given during the dark or sleep phase of the daily rhythm. The Siberian hamster is a model circadian animal except for the fact that a light treatment that gives the animal a phase advance on one day and a phase delay on the next day can result in total circadian arrhythmia for life. Once arrhythmic, the hamsters cannot learn. Learning, but not rhythmicity, is restored by short-term chronic treatment with GABA antagonists. Like many other species, if these hamsters are made arrhythmic by SCN lesion, their learning is unaffected. However, if made arrhythmic and learning disabled by the light treatment, subsequent lesions of their SCNs restore learning. SCN lesions also appear to restore learning in the Ts65Dn mice. The collective work on these two animal models of learning disability suggests that the circadian system modulates neuroplasticity. Our hypothesis is that a previously unrecognized function of the circadian system is to dampen neuroplasticity during the sleep phase to stabilize memory transcripts during their transfer to long-term memory. Thus, sleep and circadian systems have integrated roles to play in memory consolidation and do not just have separate but coincident influences on that process.

Scheduled feeding restores memory and modulates c-Fos expression in the suprachiasmatic nucleus and septohippocampal complex.

Disruptions in circadian timing impair spatial memory in humans and rodents. Circadian-arrhythmic Siberian hamsters (Phodopus sungorus) exhibit substantial deficits in spatial working memory as assessed by a spontaneous alternation (SA) task. The present study found that daily scheduled feeding rescued spatial memory deficits in these arrhythmic animals. Improvements in memory persisted for at least 3 weeks after the arrhythmic hamsters were switched back to ad libitum feeding. During ad libitum feeding, locomotor activity resumed its arrhythmic state, but performance on the SA task varied across the day with a peak in daily performance that corresponded to the previous daily window of food anticipation. At the end of scheduled feeding, c-Fos brain mapping revealed differential gene expression in entrained versus arrhythmic hamsters in the suprachiasmatic nucleus (SCN) that paralleled changes in the medial septum and hippocampus, but not in other neural structures. These data show that scheduled feeding can improve cognitive performance when SCN timing has been compromised, possibly by coordinating activity in the SCN and septohippocampal pathway.

A Novel Cooling Method and Comparison of Active Rewarming of Mildly Hypothermic Subjects.

OBJECTIVE: To compare the effectiveness of arteriovenous anastomosis (AVA) vs heated intravenous fluid (IVF) rewarming in hypothermic subjects. Additionally, we sought to develop a novel method of hypothermia induction. METHODS: Eight subjects underwent 3 cooling trials each to a core temperature of 34.8±0.6 (32.7 to 36.3°C [mean±SD with range]) by 14°C water immersion for 30 minutes, followed by walking on a treadmill for 5 minutes. Core temperatures (Δtes) and rates of cooling (°C/h) were measured. Participants were then rewarmed by 1) control: shivering only in a sleeping bag; 2) IVF: shivering in sleeping bag and infusion of 2 L normal saline warmed to 42°C at 77 mL/min; and 3) AVA: shivering in sleeping bag and circulation of 45°C warmed fluid through neoprene pads affixed to the palms and soles of the feet. RESULTS: Cold water immersion resulted in a decrease of 0.5±0.5°C Δtes and 1±0.3°C with exercise (P < .01); with an immersion cooling rate of 0.9±0.8°C/h vs 12.6±3.2°C/h with exercise (P < .001). Temperature nadir reached 35.0±0.5°C. There were no significant differences in rewarming rates between the 3 conditions (shivering: 1.3±0.7°C/h, R2 = 0.683; IVF 1.3±0.7°C/h, R2 = 0.863; and AVA 1.4±0.6°C/h, R2 = 0.853; P = .58). Shivering inhibition was greater with AVA but was not significantly different (P = .07). CONCLUSIONS: This study developed a novel and efficient model of hypothermia induction through exercise-induced convective afterdrop. Although there was not a clear benefit in either of the 2 active rewarming methods, AVA rewarming showed a nonsignificant trend toward greater shivering inhibition, which may be optimized by an improved interface.

Short-term treatment with flumazenil restores long-term object memory in a mouse model of Down syndrome.

Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABAA receptor (GABAAR) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABAAR antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS.

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-ß accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-ß oligomers.

Sleep disruption impairs haematopoietic stem cell transplantation in mice.

Many of the factors affecting the success of haematopoietic cell transplantation are still unknown. Here we show in mice that donor sleep deprivation reduces the ability of its haematopoietic stem cells (HSCs) to engraft and reconstitute the blood and bone marrow of an irradiated recipient by more than 50%. We demonstrate that sleep deprivation downregulates the expression of microRNA (miR)-19b, a negative regulator of the suppressor of cytokine signalling (SOCS) genes, which inhibit HSC migration and homing. Accordingly, HSCs from sleep-deprived mice have higher levels of SOCS genes expression, lower migration capacity in vitro and reduced homing to the bone marrow in vivo. Recovery of sleep after sleep deprivation restored the reconstitution potential of the HSCs. Taken together, this study provides insights into cellular and molecular mechanisms underlying the effects of sleep deprivation on HSCs, emphasizing the potentially critical role of donor sleep in the success of bone marrow transplantation.