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https://www.readbyqxmd.com/read/29195051/the-glymphatic-system-in-central-nervous-system-health-and-disease-past-present-and-future
#1
Benjamin A Plog, Maiken Nedergaard
The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute...
December 1, 2017: Annual Review of Pathology
https://www.readbyqxmd.com/read/29079431/voluntary-running-enhances-glymphatic-influx-in-awake-behaving-young-mice
#2
Stephanie von Holstein-Rathlou, Nicolas Caesar Petersen, Maiken Nedergaard
Vascular pathology and protein accumulation contribute to cognitive decline, whereas exercise can slow vascular degeneration and improve cognitive function. Recent investigations suggest that glymphatic clearance measured in aged mice while anesthetized is enhanced following exercise. We predicted that exercise would also stimulate glymphatic activity in awake, young mice with higher baseline glymphatic function. Therefore, we assessed glymphatic function in young female C57BL/6J mice following five weeks voluntary wheel running and in sedentary mice...
January 1, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29024871/brain-energetics-during-the-sleep-wake-cycle
#3
REVIEW
Mauro DiNuzzo, Maiken Nedergaard
Brain activity during wakefulness is associated with high metabolic rates that are believed to support information processing and memory encoding. In spite of loss of consciousness, sleep still carries a substantial energy cost. Experimental evidence supports a cerebral metabolic shift taking place during sleep that suppresses aerobic glycolysis, a hallmark of environment-oriented waking behavior and synaptic plasticity. Recent studies reveal that glial astrocytes respond to the reduction of wake-promoting neuromodulators by regulating volume, composition and glymphatic drainage of interstitial fluid...
October 9, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/28938276/anesthesia-with-dexmedetomidine-and-low-dose-isoflurane-increases-solute-transport-via-the-glymphatic-pathway-in-rat-brain-when-compared-with-high-dose-isoflurane
#4
COMPARATIVE STUDY
Helene Benveniste, Hedok Lee, Fengfei Ding, Qian Sun, Ehab Al-Bizri, Rany Makaryus, Stephen Probst, Maiken Nedergaard, Elliot A Stein, Hanbing Lu
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...
December 2017: Anesthesiology
https://www.readbyqxmd.com/read/28862640/understanding-the-functions-and-relationships-of-the-glymphatic-system-and-meningeal-lymphatics
#5
REVIEW
Antoine Louveau, Benjamin A Plog, Salli Antila, Kari Alitalo, Maiken Nedergaard, Jonathan Kipnis
Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes...
September 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28822066/do-evolutionary-changes-in-astrocytes-contribute-to-the-computational-power-of-the-hominid-brain
#6
Nancy Ann Oberheim Bush, Maiken Nedergaard
It is now well accepted that astrocytes are essential in all major nervous system functions of the rodent brain, including neurotransmission, energy metabolism, modulation of blood flow, ion and water homeostasis, and, indeed, higher cognitive functions, although the contribution of astrocytes in cognition is still in early stages of study. Here we review the most current research findings on human astrocytes, including their structure, molecular characterization, and functional properties. We also highlight novel tools that have been established for translational approaches to the comparative study of astrocytes from humans and experimental animals...
September 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28798076/perivascular-spaces-glymphatic-dysfunction-and-small-vessel-disease
#7
REVIEW
Humberto Mestre, Serhii Kostrikov, Rupal I Mehta, Maiken Nedergaard
Cerebral small vessel diseases (SVDs) range broadly in etiology but share remarkably overlapping pathology. Features of SVD including enlarged perivascular spaces (EPVS) and formation of abluminal protein deposits cannot be completely explained by the putative pathophysiology. The recently discovered glymphatic system provides a new perspective to potentially address these gaps. This work provides a comprehensive review of the known factors that regulate glymphatic function and the disease mechanisms underlying glymphatic impairment emphasizing the role that aquaporin-4 (AQP4)-lined perivascular spaces (PVSs), cerebrovascular pulsatility, and metabolite clearance play in normal CNS physiology...
September 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28736215/human-ipsc-glial-mouse-chimeras-reveal-glial-contributions-to-schizophrenia
#8
Martha S Windrem, Mikhail Osipovitch, Zhengshan Liu, Janna Bates, Devin Chandler-Militello, Lisa Zou, Jared Munir, Steven Schanz, Katherine McCoy, Robert H Miller, Su Wang, Maiken Nedergaard, Robert L Findling, Paul J Tesar, Steven A Goldman
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls...
August 3, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28627037/quantitative-gd-dota-uptake-from-cerebrospinal-fluid-into-rat-brain-using-3d-vfa-spgr-at-9-4t
#9
Hedok Lee, Kristian Mortensen, Simon Sanggaard, Palle Koch, Hans Brunner, Bjørn Quistorff, Maiken Nedergaard, Helene Benveniste
PURPOSE: We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. METHODS: We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms...
June 19, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28336567/sox9-is-an-astrocyte-specific-nuclear-marker-in-the-adult-brain-outside-the-neurogenic-regions
#10
Wei Sun, Adam Cornwell, Jiashu Li, Sisi Peng, M Joana Osorio, Nadia Aalling, Su Wang, Abdellatif Benraiss, Nanhong Lou, Steven A Goldman, Maiken Nedergaard
Astrocytes have in recent years become the focus of intense experimental interest, yet markers for their definitive identification remain both scarce and imperfect. Astrocytes may be recognized as such by their expression of glial fibrillary acidic protein, glutamine synthetase, glutamate transporter 1 (GLT1), aquaporin-4, aldehyde dehydrogenase 1 family member L1, and other proteins. However, these proteins may all be regulated both developmentally and functionally, restricting their utility. To identify a nuclear marker pathognomonic of astrocytic phenotype, we assessed differential RNA expression by FACS-purified adult astrocytes and, on that basis, evaluated the expression of the transcription factor SOX9 in both mouse and human brain...
April 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28323163/cerebrospinal-and-interstitial-fluid-transport-via-the-glymphatic-pathway-modeled-by-optimal-mass-transport
#11
Vadim Ratner, Yi Gao, Hedok Lee, Rena Elkin, Maiken Nedergaard, Helene Benveniste, Allen Tannenbaum
The glymphatic pathway is a system which facilitates continuous cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange and plays a key role in removing waste products from the rodent brain. Dysfunction of the glymphatic pathway may be implicated in the pathophysiology of Alzheimer's disease. Intriguingly, the glymphatic system is most active during deep wave sleep general anesthesia. By using paramagnetic tracers administered into CSF of rodents, we previously showed the utility of MRI in characterizing a macroscopic whole brain view of glymphatic transport but we have yet to define and visualize the specific flow patterns...
May 15, 2017: NeuroImage
https://www.readbyqxmd.com/read/28302766/cerebrospinal-fluid-clearance-in-alzheimer-disease-measured-with-dynamic-pet
#12
Mony J de Leon, Yi Li, Nobuyuki Okamura, Wai H Tsui, Les A Saint-Louis, Lidia Glodzik, Ricardo S Osorio, Juan Fortea, Tracy Butler, Elizabeth Pirraglia, Silvia Fossati, Hee-Jin Kim, Roxana O Carare, Maiken Nedergaard, Helene Benveniste, Henry Rusinek
Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with (18)F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance...
September 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28210958/does-global-astrocytic-calcium-signaling-participate-in-awake-brain-state-transitions-and-neuronal-circuit-function
#13
Celia Kjaerby, Rune Rasmussen, Mie Andersen, Maiken Nedergaard
We continuously need to adapt to changing conditions within our surrounding environment, and our brain needs to quickly shift between resting and working activity states in order to allow appropriate behaviors. These global state shifts are intimately linked to the brain-wide release of the neuromodulators, noradrenaline and acetylcholine. Astrocytes have emerged as a new player participating in the regulation of brain activity, and have recently been implicated in brain state shifts. Astrocytes display global Ca(2+) signaling in response to activation of the noradrenergic system, but whether astrocytic Ca(2+) signaling is causative or correlative for shifts in brain state and neural activity patterns is not known...
June 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28188218/focal-solute-trapping-and-global-glymphatic-pathway-impairment-in-a-murine-model-of-multiple-microinfarcts
#14
Minghuan Wang, Fengfei Ding, SaiYue Deng, Xuequn Guo, Wei Wang, Jeffrey J Iliff, Maiken Nedergaard
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 β and tau...
March 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28003156/direct-comparison-of-microglial-dynamics-and-inflammatory-profile-in-photothrombotic-and-arterial-occlusion-evoked-stroke
#15
Maria L Cotrina, Nanghong Lou, Jessica Tome-Garcia, James Goldman, Maiken Nedergaard
Many focal cerebral ischemia models utilize the middle cerebral artery occlusion (MCAO) evoked by coagulation to induce ischemic damage in the cortex and mimic the pathology observed in human patients. A second, increasingly popular model, the photothrombotic stroke, uses a laser beam to irradiate the MCA after administration of a photosensitizing dye. This widely used procedure is slowly replacing the MCAO model because of the easiness of the surgical protocol and the reproducibility of the damage. However, the photochemical reaction also results in wider microvascular injury...
February 20, 2017: Neuroscience
https://www.readbyqxmd.com/read/27931262/glymphatic-distribution-of-csf-derived-apoe-into-brain-is-isoform-specific-and-suppressed-during-sleep-deprivation
#16
Thiyagaragan M Achariyar, Baoman Li, Weiguo Peng, Philip B Verghese, Yang Shi, Evan McConnell, Abdellatif Benraiss, Tristan Kasper, Wei Song, Takahiro Takano, David M Holtzman, Maiken Nedergaard, Rashid Deane
BACKGROUND: Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it's expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel...
December 8, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27774515/a-novel-model-of-transient-occlusion-of-the-middle-cerebral-artery-in-awake-mice
#17
Lulu Xie, Hongyi Kang, Maiken Nedergaard
BACKGROUND: Stroke is one of the leading causes of death and disability worldwide. As a consequence, several excellent rodent models have been developed to gain insight into the pathophysiology of stroke and testing the efficacy of neuroprotective interventions. However, one potential problem is that albeit roughly 80% of strokes occur in awake patients, all existing murine stroke models employ anesthesia. Moreover, epidemiological studies have shown that stroke injury is more severe in the minority of patients that suffer stroke while asleep...
2016: Journal of Nature and Science
https://www.readbyqxmd.com/read/27586142/nkcc1-up-regulation-contributes-to-early-post-traumatic-seizures-and-increased-post-traumatic-seizure-susceptibility
#18
Fushun Wang, Xiaowei Wang, Lee A Shapiro, Maria L Cotrina, Weimin Liu, Ernest W Wang, Simeng Gu, Wei Wang, Xiaosheng He, Maiken Nedergaard, Jason H Huang
Traumatic brain injury (TBI) is not only a leading cause for morbidity and mortality in young adults (Bruns and Hauser, Epilepsia 44(Suppl 10):210, 2003), but also a leading cause of seizures. Understanding the seizure-inducing mechanisms of TBI is of the utmost importance, because these seizures are often resistant to traditional first- and second-line anti-seizure treatments. The early post-traumatic seizures, in turn, are a contributing factor to ongoing neuropathology, and it is critically important to control these seizures...
April 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/27499087/erythrocytes-are-oxygen-sensing-regulators-of-the-cerebral-microcirculation
#19
Helen Shinru Wei, Hongyi Kang, Izad-Yar Daniel Rasheed, Sitong Zhou, Nanhong Lou, Anna Gershteyn, Evan Daniel McConnell, Yixuan Wang, Kristopher Emil Richardson, Andre Francis Palmer, Chris Xu, Jiandi Wan, Maiken Nedergaard
Energy production in the brain depends almost exclusively on oxidative metabolism. Neurons have small energy reserves and require a continuous supply of oxygen (O2). It is therefore not surprising that one of the hallmarks of normal brain function is the tight coupling between cerebral blood flow and neuronal activity. Since capillaries are embedded in the O2-consuming neuropil, we have here examined whether activity-dependent dips in O2 tension drive capillary hyperemia. In vivo analyses showed that transient dips in tissue O2 tension elicit capillary hyperemia...
August 17, 2016: Neuron
https://www.readbyqxmd.com/read/27457281/sulforhodamine-101-a-widely-used-astrocyte-marker-can-induce-cortical-seizure-like-activity-at-concentrations-commonly-used
#20
Rune Rasmussen, Maiken Nedergaard, Nicolas Caesar Petersen
Sulforhodamine 101 (SR101) is a preferential astrocyte marker widely used in 2-photon microscopy experiments. Here we show, that topical loading of two commonly used SR101 concentrations, 100 μM and 250 μM when incubated for 10 min, can induce seizure-like local field potential (LFP) activity in both anaesthetized and awake mouse sensori-motor cortex. This cortical seizure-like activity develops in less than ten minutes following topical loading, and when applied longer, these neuronal discharges reliably evoke contra-lateral hindlimb muscle contractions...
July 26, 2016: Scientific Reports
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