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.

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.

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.

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.

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.

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.

Drainage of senescent astrocytes from brain via meningeal lymphatic routes.

Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C-C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.

Decreased blood CD4+ T lymphocyte helps predict cognitive impairment in patients with amyotrophic lateral sclerosis.

BACKGROUND: ALS patients have changed peripheral immunity. It is unknown whether peripheral immunity is related to cognitive dysfunction in ALS patients. OBJECTIVE: To explore the relationship between the peripheral blood lymphocyte subsets and the cognitive status in ALS patients. METHODS: Among 81 ALS patients, we compared the demographic, clinical, and peripheral levels of total T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, B lymphocyte, and NK cell between those with cognitive impairment (ALS-ci) and those without (ALS-nci). The cognitive status was evaluated via the Chinese version of the Edinburgh cognitive and behavioral screen (ECAS). Significant predictors of cognitive impairment in univariate logistic regression analysis were further examined using multivariate logistic regression analysis. RESULTS: 39.5% of all ALS patients had cognitive impairment. The ALS-ci group had shorter education time, older age at both symptom onset and testing, longer disease duration, and lower levels of peripheral total, CD4+, and CD8+ T lymphocyte and B lymphocyte than the ALS-nci group. Frequency of behavioral impairment did not differ between the two groups. While parameters with significant differences identified by group comparison were also significant predictors of cognitive impairment in univariate logistic regression analysis except the level of B lymphocyte, only older age at testing, education time less than 9 years, and lower level of CD4+ T lymphocyte remained significant in multivariate logistic regression analysis. The predictive model combining these three parameters had an area under the receiver operating characteristic curve value of 0.842 with a sensitivity of 90.6% and a specificity of 67.3%. CONCLUSION: In Chinese ALS patients, blood CD4+ T lymphocyte might help evaluate cognitive impairment along with age and education level.

[The role of androgen in male sexual arousal].

Sexual arousal is an important factor for the success of sexual behavior, and regulated by the central nervous system, its underlying mechanism is very complicated. Androgen is the most important endocrine hormone in men, which is deeply involved in the whole process of male sexual response, but how it regulates male sexual arousal has not been fully clarified and remains one of the hotspots in current andrological research. Therefore, this paper presents an overview of the advances in the studies of the related role and mechanism of androgen in male sexual arousal. In the central nervous system, androgen regulates the release of dopamine neurotransmitters by binding androgen receptors or metabolizing neurosteroids, thus activating the brain reward system. Besides, androgen regulates the neuronal plasticity and spinous process formation in the neural circuit of sexual arousal to ensure successful activation and conduction of the neural circuit. However, the specific regulating mechanism of sexual arousal remains to be further explored.

Microglial Hv1 proton channels promote white matter injuries after chronic hypoperfusion in mice.

Microglia are critical in damage/repair processes during ischemic white matter injury (WMI). Voltage-gated proton channel (Hv1) is expressed in microglia and contributes to nicotinamide adenine dinucleotide phosphate oxidase complex-dependent production of reactive oxygen species (ROS). Recent findings have shown that Hv1 is involved in regulating luminal pH of M1-polarized microglial phagosomes and inhibits endocytosis in microglia. We previously reported that Hv1 facilitated production of ROS and pro-inflammatory cytokines in microglia and enhanced damage to oligodendrocyte progenitor cells from oxygen and glucose deprivation. To investigate the role of Hv1 in hypoperfusion-induced WMI, we employed mice that were genetically devoid of Hv1 (Hv1-/- ), as well as a model of subcortical vascular dementia via bilateral common carotid artery stenosis. Integrity of myelin was assessed using immunofluorescent staining and transmission electron microscopy, while cognitive impairment was assessed using an eight-arm radial maze test. Hv1 deficiency was found to attenuate bilateral common carotid artery stenosis-induced disruption of white matter integrity and impairment of working memory. Immunofluorescent staining and western blotting were used to assay changes in oligodendrocytes, OPCs, and microglial polarization. Compared with that in wild-type (WT) mice, Hv1-/- mice exhibited reduced ROS generation, decreased pro-inflammatory cytokines production, and an M2-dominant rather than M1-dominant microglial polarization. Furthermore, Hv1-/- mice exhibited enhanced OPC proliferation and differentiation into oligodendrocytes. Results of mouse-derived microglia-OPC co-cultures suggested that PI3K/Akt signaling was involved in Hv1-deficiency-induced M2-type microglial polarization and concomitant OPC differentiation. These results suggest that microglial Hv1 is a promising therapeutic target for reducing ischemic WMI and cognitive impairment.

Sensation of TRPV1 via 5-hydroxytryptamine signaling modulates pain hypersensitivity in a 6-hydroxydopamine induced mice model of Parkinson's disease.

Parkinson's disease (PD) related pain can be assigned to either nociceptive pain or neuropathic pain, in which Transient receptor potential vanilloid 1 (TRPV1) has been demonstrated to play a pivotal role. Yet little research has examined possible involvement of TRPV1 in pain in PD. Here, we show that TRPV1 is highly expressed in PD and blocking TRPV1 can alleviate pain in PD. The level of TRPV1 in 6-OHDA induced semi mice model of PD was evaluated. The effect of TRPV1 and involved serotonin (5-HT) was also examined in the model. Unilateral injection of 6-OHDA in striatum significantly decreased thermal pain threshold and induced mechanical allodynia without changes in conditioned place preference. Immunostaining revealed that great increased expression in TRPV1 in the Vc of 6-OHDA lesioned mice compared with sham mice. TRPV1 sensitization was maintained by 5-HT/5-HT3A. In 6-OHDA-lesioned mice model of PD, TRPV1 sensitization might be implicated in the maintenance of behavioral hypersensitivity by enhanced descending 5-HT pain facilitation and dorsal horn 5-HT3AR mechanism.

Deficiency of the microglial Hv1 proton channel attenuates neuronal pyroptosis and inhibits inflammatory reaction after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) causes neurological dysfunction with devastating consequences. SCI pathogenesis is accompanied by inflammasome activation and neuronal damage. But the spatial pattern and the time course of neuronal pyroptosis and apoptosis after SCI should be further elucidated. The microglial voltage-gated proton channel (Hv1) is implicated in reactive oxygen species (ROS)-induced neuronal damage following ischemic stroke. However, there is a lack of quantification on the neuronal pyroptosis and apoptosis associated with microglial Hv1 after SCI. METHODS: We analyzed spatial and temporal characteristics of neuronal pyroptosis and apoptosis following SCI and investigated the effects of Hv1 deficiency on neuronal pyroptosis and the nod-like receptor 3 (NLRP3) inflammasome pathway by using a mouse model of SCI. We tested the effects of Hv1-deficient microglia on ROS production in vivo and examined the relationship between ROS and neuronal pyroptosis in vitro. RESULTS: We observed that apoptosis was detected closer to the injury core than pyroptosis. The incidence of neuronal apoptosis peaked on day 1 after SCI and occurred before pyroptosis. Hv1 deficiency reduced neuronal apoptosis and NLRP3-inflammasome-mediated pyroptosis, improved axonal regeneration, and reduced motor deficits. SCI led to elevated ROS levels, whereas Hv1 deficiency downregulated microglial ROS generation. In vitro, ROS upregulated neuronal pyroptosis and activated the NLRP3 inflammasome pathway, both of which were reversed by addition of a ROS scavenger. Our results suggested that microglial Hv1 regulated neuronal apoptosis and NLRP3-induced neuronal pyroptosis after SCI by mediating ROS production. CONCLUSION: Following SCI, neuronal pyroptosis lasted longer and occurred farther away from the injury core compared with that of neuronal apoptosis. Microglial Hv1 deficiency downregulated microglial ROS generation and reduced apoptosis and NLRP3-induced neuronal pyroptosis. Our findings may provide novel insights into Hv1-associated mechanisms underlying neuronal damage after SCI.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid ß and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation.SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid ß. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.

Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane.

BACKGROUND: The glymphatic pathway transports cerebrospinal fluid through the brain, thereby facilitating waste removal. A unique aspect of this pathway is that its function depends on the state of consciousness of the brain and is associated with norepinephrine activity. A current view is that all anesthetics will increase glymphatic transport by inducing unconsciousness. This view implies that the effect of anesthetics on glymphatic transport should be independent of their mechanism of action, as long as they induce unconsciousness. We tested this hypothesis by comparing the supplementary effect of dexmedetomidine, which lowers norepinephrine, with isoflurane only, which does not. METHODS: Female rats were anesthetized with either isoflurane (N = 8) or dexmedetomidine plus low-dose isoflurane (N = 8). Physiologic parameters were recorded continuously. Glymphatic transport was quantified by contrast-enhanced magnetic resonance imaging. Cerebrospinal fluid and gray and white matter volumes were quantified from T1 maps, and blood vessel diameters were extracted from time-of-flight magnetic resonance angiograms. Electroencephalograms were recorded in separate groups of rats. RESULTS: Glymphatic transport was enhanced by 32% in rats anesthetized with dexmedetomidine plus low-dose isoflurane when compared with isoflurane. In the hippocampus, glymphatic clearance was sixfold more efficient during dexmedetomidine plus low-dose isoflurane anesthesia when compared with isoflurane. The respiratory and blood gas status was comparable in rats anesthetized with the two different anesthesia regimens. In the dexmedetomidine plus low-dose isoflurane rats, spindle oscillations (9 to 15 Hz) could be observed but not in isoflurane anesthetized rats. CONCLUSIONS: We propose that anesthetics affect the glymphatic pathway transport not simply by inducing unconsciousness but also by additional mechanisms, one of which is the repression of norepinephrine release.

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aß in Alzheimer's disease (AD). In wild type mice, we show that Aß40 (fluorescently labeled Aß40 or unlabeled Aß40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aß42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aß40. Interestingly, pretreatment with Aß40 in the CSF, but not Aß42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-ß deposits, glymphatic transport was reduced, due to the accumulation of toxic Aß species, such as soluble oligomers. CSF-derived Aß40 co-localizes with existing endogenous vascular and parenchymal amyloid-ß plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aß accumulation. Importantly, glymphatic failure preceded significant amyloid-ß deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.

Impairment of paravascular clearance pathways in the aging brain.

OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-ß was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTERPRETATION: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.

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.

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.

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.

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.