Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice.

Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease.

Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.

Effects of chronotype on sleep, mood and cardiovascular circadian rhythms in rotating night shift medical workers.

PURPOSE: Whether chronotype affects the health outcomes of night shift work populations is unknown. This study aimed to assess the influence of different chronotypes in the rotating night shift population on sleep status, mood, blood pressure (BP), and heart rate variability (HRV), as well as the circadian rhythm of BP and HRV. METHODS: A total of 208 rotating night shift workers were included. All participants completed structured questionnaires to assess chronotype, mood and sleep status. During their daily lives outside of the night shift, they underwent 24-hour Holter electrocardiogram monitoring and 24-hour ambulatory blood pressure monitoring. Day-time and night-time BP and BP dipping were obtained. Day-time and night-time HRV values (SDNN, RMSSD, LF, HF, LF nu, SD1, SD2 and SD2/SD1) were calculated and fitted to the cosine period curve. Three circandian parameters (mesor, amplitude and acrophase) were extracted to quantify the circadian rhythm of the HRV indices. RESULTS: Among all three groups, E-type showed more fatigue and sleepiness. In addition, E-type showed blunted diastolic BP dipping. Notably, E-type showed association with higher RMSSD, LF, HF and SD1 in the night time, and higher mesors of RMSSD and LF and amplitude of SD2/SD1 in circadian analysis. CONCLUSION: Chronotype is a factor affecting fatigue, sleepiness and cardiovascular circadian rhythms of rotating night shift workers. Chronotype should be taken into consideration for managing night-shift rotation to promote occupational health.

Sleep-phasic heart rate variability predicts stress severity: Building a machine learning-based stress prediction model.

We propose a novel approach for predicting stress severity by measuring sleep phasic heart rate variability (HRV) using a smart device. This device can potentially be applied for stress self-screening in large populations. Using a Holter electrocardiogram (ECG) and a Huawei smart device, we conducted 24-h dual recordings of 159 medical workers working regular shifts. Based on photoplethysmography (PPG) and accelerometer signals acquired by the Huawei smart device, we sorted episodes of cyclic alternating pattern (CAP; unstable sleep), non-cyclic alternating pattern (NCAP; stable sleep), wakefulness, and rapid eye movement (REM) sleep based on cardiopulmonary coupling (CPC) algorithms. We further calculated the HRV indices during NCAP, CAP and REM sleep episodes using both the Holter ECG and smart-device PPG signals. We later developed a machine learning model to predict stress severity based only on the smart device data obtained from the participants along with a clinical evaluation of emotion and stress conditions. Sleep phasic HRV indices predict individual stress severity with better performance in CAP or REM sleep than in NCAP. Using the smart device data only, the optimal machine learning-based stress prediction model exhibited accuracy of 80.3 %, sensitivity 87.2 %, and 63.9 % for specificity. Sleep phasic heart rate variability can be accurately evaluated using a smart device and subsequently can be used for stress predication.

Sleep fragmentation reduces explorative behaviors and impairs motor coordination in male mice.

Sleep fragmentation (SF), which refers to discontinuous and fragmented sleep, induces cognitive impairment and anxiety-like behavior in mice. However, whether SF can affect motor capability in healthy young wild-type mice and the underlying mechanisms remain unknown. We performed seven days of sleep fragmentation (SF 7d) interventions in young wild-type male mice. While SF mice experienced regular sleep disruption between Zeitgeber time (ZT) 0-12, control mice were allowed to have natural sleep (NS) cycles. Homecage analysis and conventional behavioral tests were conducted to assess the behavioral alterations in behavioral patterns in general and motor-related behaviors. Sleep structures and the power spectrum of electroencephalograms (EEGs) were compared between SF 7d and NS groups. Neuronal activation was measured using c-Fos immunostaining and quantified in multiple brain regions. SF of 7 days significantly decreased bouts of rearing and sniffing and the duration of rearing and impaired motor coordination. An increase in the total sleep time and a decrease in wakefulness between ZT12-24 was found in SF 7d mice. In SF 7d mice, EEG beta1 power was increased in rapid eye movement (REM) sleep while theta power was decreased during wakefulness. SF 7d resulted in significant suppression in c-Fos (+) cell counts in the motor cortex and hippocampus but an increase in c-Fos (+) cell counts in the substantia nigra pars compacta (SNc). In summary, SF 7d suppressed explorative behaviors and impaired motor coordination as compared to NS. EEG power and altered neuronal activity detected by c-Fos staining might contribute to the behavioral changes.

Association of intra-shift nap duration with heart rate variability in medical night shift workers.

Napping during night shifts effectively reduces disease risk and improves work performance, but few studies have investigated the association between napping and physiological changes, particularly in off-duty daily lives. Changes in the autonomic nervous system precede diseases like cardiovascular disease, diabetes, and obesity. Heart rate variability is a good indicator of autonomic nervous system. This study aimed to investigate the link between night shift nap durations and heart rate variability indices in the daily lives of medical workers. As indicators of chronic and long-term alterations, the circadian patterns of heart rate variability indices were evaluated. We recruited 146 medical workers with regular night shifts and divided them into four groups based on their self-reported nap durations. Heart rate variability circadian parameters (midline-estimating statistic of rhythm, amplitude, and acrophase) were obtained by obtaining 24-h electrocardiogram on a day without night shifts, plotting the data of the heart rate variability indices as a function of time, and fitting them into periodic cosine curves. Using clinical scales, depression, anxiety, stress, fatigue, and sleepiness were assessed. Linear regression analysis revealed a positive relationship between 61-120-min naps and 24-h, daytime, and night-time heart rate variability indices, and the parasympathetic activity oscillation amplitude (indexed by high-frequency power, the square root of the mean of the sum of squares of differences between adjacent normal intervals, standard deviation of short-term R-R-interval variability) within one circadian cycle. This study indicated that napping for 61-120 min during night shifts could benefit medical workers' health, providing physiological evidence to promote nap management.

Complex interactive multimodal intervention to improve personalized stress management among healthcare workers in China: A knowledge translation protocol.

Objectives: Numerous stress management interventions have been implemented in the workplace, but few are adapted to the healthcare setting. Due to the nature of their jobs, healthcare workers (HCWs) may find it difficult to adopt recommended stress management strategies. We present the protocol for a 12-week personalized stress management intervention among HCWs to change their behavior as well as improve physiological/psychological outcomes. Methods: It is a pragmatic quasi-experimental study involving stressed HCWs from two general hospitals in Wuhan, China. The intervention group will receive a complex interactive multimodal intervention, including advanced education via mobile connection, participation in a web-based social network, tailored feedback, and the support of a nurse coach, while the control group will engage in self-guided stress management. Results: The primary outcome is centered on behavioral measures, namely improvements in stress management practice frequency after a 12-week intervention. The secondary outcomes are the changes in stress-related physiological indices (i.e. high frequency variability and normalized unit assessed by Holter) and psychological indicators (scores on the Perceived Stress Scale and Depression, Anxiety, Stress Scale) following 12 weeks of treatment. Conclusion: The knowledge translation intervention builds on a body of work defining the role of individualized instruction and feedback intervention, as well as group intervention through WeChat social network and personalized coaching. We believe this novel intervention will help HCWs promote their stress management awareness and skills, and ultimately benefit their long-term health. Trial Registration: ClinicalTrials.gov., NCT05239065. Registered 14 February 2022-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05239065.

Durative sleep fragmentation with or without hypertension suppress rapid eye movement sleep and generate cerebrovascular dysfunction.

Either hypertension or chronic insomnia is the risk factor of developing vascular dementia. Durative hypertension can induce vascular remodeling and is used for modeling small vessel disease in rodents. It remains undetermined if the combination of hypertension and sleep disturbance exacerbates vascular dysfunction or pathologies. Previously, we found chronic sleep fragmentation (SF) dampened cognition in young mice without disease predispositions. In the current study, we superimposed SF with hypertension modeling in young mice. Angiotensin II (AngII)-releasing osmotic mini pumps were subcutaneously implanted to generate persistent hypertension, while sham surgeries were performed as controls. Sleep fragmentation with repetitive arousals (10 s every 2 min) during light-on 12 h for consecutive 30 days, while mice undergoing normal sleep (NS) processes were set as controls. Sleep architectures, whisker-stimulated cerebral blood flow (CBF) changes, vascular responsiveness as well as vascular pathologies were compared among normal sleep plus sham (NS + sham), SF plus sham (SF + sham), normal sleep plus AngII (NS + AngII), and SF plus AngII (SF + AngII) groups. SF and hypertension both alter sleep structures, particularly suppressing REM sleep. SF no matter if combined with hypertension strongly suppressed whisker-stimulated CBF increase, suggesting the tight association with cognitive decline. Hypertension modeling sensitizes vascular responsiveness toward a vasoactive agent, Acetylcholine (ACh, 5 mg/ml, 10 µl) delivered via cisterna magna infusion, while SF exhibits a similar but much milder effect. None of the modeling above was sufficient to induce arterial or arteriole vascular remodeling, but SF or SF plus hypertension increased vascular network density constructed by all categories of cerebral vessels. The current study would potentially help understand the pathogenesis of vascular dementia, and the interconnection between sleep and vascular health.

Astrocyte-Derived Exosomes Contribute to Pathologies of Neuromyelitis Optica Spectrum Disorder in Rodent Model.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin-4 autoantibodies (AQP4-IgG, named as NMO-IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO-IgG, the pathogenic astrocyte-derived exosomes are released and injure the neighboring cells. METHODS: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte-derived exosomes (AST-ExosNMO vs AST-ExosCON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST-ExosNMO . The microRNA (miRNA) sequencing of AST-Exos and verification were performed to identify the key pathogenic miRNA. The custom-designed adeno-associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. RESULTS: AST-ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR-129-2-3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR-129-2-3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR-129-2-3p level was significantly elevated in NMOSD patients and correlated with disease severity. INTERPRETATION: Astrocytes targeted by NMO-IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163-181.

Updated Understanding of the Glial-Vascular Unit in Central Nervous System Disorders.

The concept of the glial-vascular unit (GVU) was raised recently to emphasize the close associations between brain cells and cerebral vessels, and their coordinated reactions to diverse neurological insults from a "glio-centric" view. GVU is a multicellular structure composed of glial cells, perivascular cells, and perivascular space. Each component is closely linked, collectively forming the GVU. The central roles of glial and perivascular cells and their multi-level interconnections in the GVU under normal conditions and in central nervous system (CNS) disorders have not been elucidated in detail. Here, we comprehensively review the intensive interactions between glial cells and perivascular cells in the niche of perivascular space, which take part in the modulation of cerebral blood flow and angiogenesis, formation of the blood-brain barrier, and clearance of neurotoxic wastes. Next, we discuss dysfunctions of the GVU in various neurological diseases, including ischemic stroke, spinal cord injury, Alzheimer's disease, and major depression disorder. In addition, we highlight the possible therapies targeting the GVU, which may have potential clinical applications.

Relations among perceived stress, fatigue, and sleepiness, and their effects on the ambulatory arterial stiffness index in medical staff: A cross-sectional study.

Objective: To explore the relations among perceived stress, fatigue, sleepiness, and the pathway of their effects on the ambulatory arterial stiffness index (AASI) among medical staff. Methods: This cross-sectional study was conducted at a tertiary hospital in Wuhan, China. Perceived stress, fatigue, and sleepiness were measured using the perceived stress scale (PSS), Fatigue assessment scale (FAS), and Epworth Sleepiness Scale (ESS), respectively. AASI was obtained from 24-h ambulatory blood pressure monitoring. Path analysis was used to clarify the relations among the PSS, FAS, and ESS scores, and their relations to AASI values. Results: A total of 153 participants were included herein. The PSS and FAS correlated with the ESS (r = 0.424, p < 0.001), and the PSS correlated with the FAS (r = 0.614, p < 0.001). In addition, the ESS correlated with the AASI (r = 0.225, p = 0.005). According to the path analysis results, the PSS and FAS had no direct effect on the AASI, but did have an indirect effect on this index (ß = 0.059, 95% confidence interval [CI] = 0.017-0.128, p = 0.005; ß = 0.059, 95%CI = 0.016-0.135, p = 0.006, respectively) by influencing the ESS (ß = 0.263, ß = 0.262, p = 0.004). Conclusion: Sleepiness was a mediator of the effects of perceived stress and fatigue on AASI.

Correlation of Circadian Rhythms of Heart Rate Variability Indices with Stress, Mood, and Sleep Status in Female Medical Workers with Night Shifts.

Purpose: Heart rate variability (HRV) indices have been used as stress indicators. Rare studies investigated the associations of circadian rhythms of the HRV indices with the stress, mood, and sleep conditions in populations under stress. Methods: In total 257 female participants (203 shift workers and 54 non-shift workers) were included. All the participants completed a structured questionnaire to assess the stress, mood, and sleep conditions and performed 24-hour Holter electrocardiogram monitoring on the day away from shifts. Using epochs of 1-min or 5-min beat-to-beat intervals, the HRV indices (SDNN, RMSSD, LF, HF, LF/HF, and LFnu, SD1, SD2, SD1/SD2) were plotted as a function of time and fitted into cosine periodic curves, respectively. Three mathematical parameters based on the cosine periodic curves were extracted, MESOR (M, overall averages of the cosine curve), amplitude (A, amplitude of the peak of the cosine curve), and acrophase (θ, latency to the peak) to quantify the circadian rhythms of the HRV indices. Multivariable linear regression models were used to reveal the associations of these parameters with the clinical assessments of stress, mood, or sleep conditions, as well as with the 24-h averages of the HRV indices. Results: The parameters M and A of SDNN, RMSSD, LF, and HF, and θ of LF/HF and LFnu significantly differ between shift and non-shift workers. The parameter θ of LF/HF positively correlates with the severity of stress and anxiety. The parameter A of LF/HF and LFnu also positively correlates with daytime sleepiness and sleep fragmentation. In addition, the parameters M and A instead of θ of SDNN, RMSSD, LF, LF/HF, and LFnu significantly correlate with the 24-h averages of HRV indices. Conclusion: The circadian rhythms of the HRV indices over 24 hours can, to some extent, predict the severity of stress, emotion and sleep conditions in female populations under stress.

Optic nerve head: A gatekeeper for vitreous infectious insults?

The axons of retinal ganglion cells (RGCs) pass through the optic nerve head (ONH) and form the optic nerve (ON). The ONH serves as an anatomical interface between the vitreous cavity and subarachnoid space. After inducing acute neuroinflammation by intravitreal injection of lipopolysaccharides (LPS), we observed inflammatory activation in the retina, but detect no signs of inflammation in the posterior ON or infiltration of inflammatory cells in the ONH. Therefore, we hypothesized that the ONH functions as a barrier to vitreous inflammation. Using transmission electron microscopy, we identified significant increase in G-ratio in the posterior ON on day 7 post intravitreal injection (PII) of LPS compared with the phosphate buffered saline (PBS) group. Moreover, using confocal imaging of ex vivo tissue extracted from Aldh1L1-eGFP reporter mice, we observed that the ONH astrocytes altered their spatial orientation by elongating their morphology along the axonal axis of RGCs in LPS- versus PBS-treated eyes; this was quantified by the ratio of longitudinal (DL) and transverse (DT) diameter of astrocytes and the proportion of longitudinally locating astrocytes. Supportive evidences were further provided by transmission electron microscopic imaging in rat ONH. We further conducted RNA sequencing of ONH on day 1 PII and found LPS induced clear upregulation of immune and inflammatory pathways. Furthermore, gene set enrichment analysis revealed that astrocyte and microglia contributed prominently to the transcriptomic alterations in ONH. Here, we report that the vitreous infectious insults induce morphological changes of ONH astrocytes and transcriptomic alterations in the ONH. Glial responses in the ONH may defend against vitreous infectious insults and serve as a barrier to inflammation for the central nervous system.

The Effect of Perceived Stress, Family Companionship, and Mental Health on the Subjective Happiness of Chinese Healthcare Workers: A Mixed Research Method.

Aim: This study aimed to understand the impact of perceived stress on the subjective happiness of Chinese healthcare workers (HCWs) and to further explore the chain-mediating role of family companionship and mental health. Background: In the face of tense doctor-patient relationships; a heavy workload; long working hours; seemingly endless shifts; potential professional title promotions; work performance assessments; and the difficult balance between family, work, and other aspects of life, HCWs are often under great pressure, which can endanger mental health and reduce subjective happiness. However, the role of healthcare workers' active participation in family companionship in mental health and subjective happiness is not clear. Method: We used a mixed research design to collect data in two locations (Hospital A and Hospital B) in Wuhan, China. A self-distributed questionnaire was assigned to HCWs through the Research Electronic Data Capture survey. A total of 368 valid surveys were obtained. Results: Hospital A's perceived stress level and mental health problems were more severe, while Hospital B had a higher subjective happiness score and more time to spend with their families. Subjective happiness was affected by children, education, occupation, health status, commuting time, and the scores of perceived stress and depression. The scores of perceived stress and mental health were significantly negatively associated with subjective happiness and family companionship, and there was a significant positive correlation between subjective happiness and family companionship. The results also showed that family companionship and mental health acted as serial mediators between perceived stress and subjective happiness. However, family companionship did not play a mediating role between perceived stress and subjective happiness. Most HCWs had work-family conflicts, and a high amount of work pressure and feelings of powerlessness and not having sufficient time were common when they accompanied their families. Conclusions: HCWs had a high level of perceived stress and psychological distress, and their subjective happiness score was lower than that of the general population. Many HCWs experienced negative emotions when taking care of their families. Only a small number of people had enough time to spend time with their families and perform more prominently in busier hospitals. More importantly, perceived stress can indirectly have an impact on subjective happiness through a chain-mediating effect of family companionship and mental health, and family companionship may not always promote subjective happiness unless mental health is maintained. Therefore, in the future, we can consider carrying out interventions based on family companionship and mental health among HCWs to promote the healthy and harmonious development of individuals, families, and hospitals.

A cluster of mesopontine GABAergic neurons suppresses REM sleep and curbs cataplexy.

Physiological rapid eye movement (REM) sleep termination is vital for initiating non-REM (NREM) sleep or arousal, whereas the suppression of excessive REM sleep is promising in treating narcolepsy. However, the neuronal mechanisms controlling REM sleep termination and keeping sleep continuation remain largely unknown. Here, we reveal a key brainstem region of GABAergic neurons in the control of both physiological REM sleep and cataplexy. Using fiber photometry and optic tetrode recording, we characterized the dorsal part of the deep mesencephalic nucleus (dDpMe) GABAergic neurons as REM relatively inactive and two different firing patterns under spontaneous sleep-wake cycles. Next, we investigated the roles of dDpMe GABAergic neuronal circuits in brain state regulation using optogenetics, RNA interference technology, and celltype-specific lesion. Physiologically, dDpMe GABAergic neurons causally suppressed REM sleep and promoted NREM sleep through the sublaterodorsal nucleus and lateral hypothalamus. In-depth studies of neural circuits revealed that sublaterodorsal nucleus glutamatergic neurons were essential for REM sleep termination by dDpMe GABAergic neurons. In addition, dDpMe GABAergic neurons efficiently suppressed cataplexy in a rodent model. Our results demonstrated that dDpMe GABAergic neurons controlled REM sleep termination along with REM/NREM transitions and represented a novel potential target to treat narcolepsy.

Natural killer cells-related immune traits and amyotrophic lateral sclerosis: A Mendelian randomization study.

Background: Observational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear. Objective: This study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS. Materials and methods: Single nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3- lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3- lymphocytes, and the median fluorescence intensities of CD16-CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method. Results: Each one standard deviation increase in the expression levels of CD16-CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected. Conclusion: Our results suggest that higher expression levels of CD16-CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

Locomotor Hyperactivity in the Early-Stage Alzheimer's Disease-like Pathology of APP/PS1 Mice: Associated with Impaired Polarization of Astrocyte Aquaporin 4.

Non-cognitive behavioral and psychological symptoms often occur in Alzheimer's disease (AD) patients and mouse models, although the exact neuropathological mechanism remains elusive. Here, we report hyperactivity with significant inter-individual variability in 4-month-old APP/PS1 mice. Pathological analysis revealed that intraneuronal accumulation of amyloid-ß (Aß), c-Fos expression in glutamatergic neurons and activation of astrocytes were more evident in the frontal motor cortex of hyperactive APP/PS1 mice, compared to those with normal activity. Moreover, the hyperactive phenotype was associated with mislocalization of perivascular aquaporin 4 (AQP4) and glymphatic transport impairment. Deletion of the AQP4 gene increased hyperactivity, intraneuronal Aß load and glutamatergic neuron activation, but did not influence working memory or anxiety-like behaviors of 4-month-old APP/PS1 mice. Together, these results demonstrate that AQP4 mislocalization or deficiency leads to increased intraneuronal Aß load and neuronal hyperactivity in the motor cortex, which in turn causes locomotor over-activity during the early pathophysiology of APP/PS1 mice. Therefore, improving AQP4 mediated glymphatic clearance may offer a new strategy for early intervention of hyperactivity in the prodromal phase of AD.

Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine.

Sleep has a complex micro-architecture, encompassing micro-arousals, sleep spindles and transitions between sleep stages. Fragmented sleep impairs memory consolidation, whereas spindle-rich and delta-rich non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep promote it. However, the relationship between micro-arousals and memory-promoting aspects of sleep remains unclear. In this study, we used fiber photometry in mice to examine how release of the arousal mediator norepinephrine (NE) shapes sleep micro-architecture. Here we show that micro-arousals are generated in a periodic pattern during NREM sleep, riding on the peak of locus-coeruleus-generated infraslow oscillations of extracellular NE, whereas descending phases of NE oscillations drive spindles. The amplitude of NE oscillations is crucial for shaping sleep micro-architecture related to memory performance: prolonged descent of NE promotes spindle-enriched intermediate state and REM sleep but also associates with awakenings, whereas shorter NE descents uphold NREM sleep and micro-arousals. Thus, the NE oscillatory amplitude may be a target for improving sleep in sleep disorders.