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Cerebrospinal fluid (CSF) is an essential and critical component of the central nervous system (CNS). According to the concept of the "third circulation" originally proposed by Cushing, CSF is mainly produced by the choroid plexus and subsequently leaves the cerebral ventricles via the foramen of Magendie and Luschka. CSF then fills the subarachnoid space from whence it disperses to all parts of the CNS, including the forebrain and spinal cord. CSF provides buoyancy to the submerged brain, thus protecting it against mechanical injury. CSF is also transported via the glymphatic pathway to reach deep interstitial brain regions along perivascular channels; this CSF clearance pathway promotes transport of energy metabolites and signaling molecules, and the clearance of metabolic waste. In particular, CSF is now intensively studied as a carrier for the removal of proteins implicated in neurodegeneration, such as amyloid-β and tau. Despite this key function of CSF, there is little information about its production rate, the factors controlling CSF production, and the impact of diseases on CSF flux. Therefore, we consider it to be a matter of paramount importance to quantify better the rate of CSF production, thereby obtaining a better understanding of CSF dynamics. To this end, we now review the existing methods developed to measure CSF production, including invasive, noninvasive, direct, and indirect methods, and MRI-based techniques. Depending on the methodology, estimates of CSF production rates in a given species can extend over a ten-fold range. Throughout this review, we interrogate the technical details of CSF measurement methods and discuss the consequences of minor experimental modifications on estimates of production rate. Our aim is to highlight the gaps in our knowledge and inspire the development of more accurate, reproducible, and less invasive techniques for quantitation of CSF production., (© 2022. The Author(s).)

Throughout the nervous system, ion gradients drive fundamental processes. Yet, the roles of interstitial ions in brain functioning is largely forgotten. Emerging literature is now revitalizing this area of neuroscience by showing that interstitial cations (K + , Ca 2+ and Mg 2+ ) are not static quantities but change dynamically across states such as sleep and locomotion. In turn, these state-dependent changes are capable of sculpting neuronal activity; for example, changing the local interstitial ion composition in the cortex is sufficient for modulating the prevalence of slow-frequency neuronal oscillations, or potentiating the gain of visually evoked responses. Disturbances in interstitial ionic homeostasis may also play a central role in the pathogenesis of central nervous system diseases. For example, impairments in K + buffering occur in a number of neurodegenerative diseases, and abnormalities in neuronal activity in disease models disappear when interstitial K + is normalized. Here we provide an overview of the roles of interstitial ions in physiology and pathology. We propose the brain uses interstitial ion signaling as a global mechanism to coordinate its complex activity patterns, and ion homeostasis failure contributes to central nervous system diseases affecting cognitive functions and behavior., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na + /K + /2Cl - cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord., Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy., Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature., Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system.

Microglia constitute as much as 10-15% of all cells in the mammalian central nervous system (CNS) and are the only glial cells that do not arise from the neuroectoderm. As the principal CNS immune cells, microglial cells represent the first line of defence in response to exogenous threats. Past studies have largely been dedicated to defining the complex immune functions of microglial cells. However, our understanding of the roles of microglia has expanded radically over the past years. It is now clear that microglia are critically involved in shaping neural circuits in both the developing and adult CNS, and in modulating synaptic transmission in the adult brain. Intriguingly, microglial cells appear to use the same sets of tools, including cytokine and chemokine release as well as phagocytosis, whether modulating neural function or mediating the brain's innate immune responses. This review will discuss recent developments that have broadened our views of neuro-glial signalling to include the contribution of microglial cells., (© 2014 The Author(s) Published by the Royal Society. All rights reserved.)

Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Chloride (Cl−) is the major central nervous system (CNS) anion mediating inhibitory neurotransmission. Astrocytes are key homoeostatic glial cells populating the CNS, although the role of these cells in regulating excitatory-inhibitory balance remains unexplored. Here we show that astrocytes act as a dynamic Cl− reservoir regulating Cl− homoeostasis in the CNS. We found that intracellular chloride concentration ([Cl−]i) in astrocytes is high and stable during sleep. In awake mice astrocytic [Cl−]i is lower and exhibits large fluctuation in response to both sensory input and motor activity. Optogenetic manipulation of astrocytic [Cl−]i directly modulates neuronal activity during locomotion or whisker stimulation. Astrocytes thus serve as a dynamic source of extracellular Cl− available for GABAergic transmission in awake mice, which represents a mechanism for modulation of the inhibitory tone during sustained neuronal activity. Astrocytes act as a dynamic Cl− reservoir regulating Cl− homeostasis in the CNS. Astrocytic Cl− is high and stable during sleep, it is lower during wakefulness and fluctuates in response to sensory input and motor activity. Efflux of Cl− from astrocytes supports inhibitory transmission in the CNS. [ABSTRACT FROM AUTHOR]

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na+/K+/2Cl− cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord. Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy. Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature. Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system. [ABSTRACT FROM AUTHOR]

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. Understanding the differences in astrocytes is essential to elucidate the contribution of astrocytes to normal physiology, cognitive processing and diverse pathologies of the central nervous system. [ABSTRACT FROM AUTHOR]

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. This review also discusses the implications that glymphatic impairment may have on SVD inception and progression with the aim of exploring novel therapeutic targets and highlighting the key questions that remain to be answered. [ABSTRACT FROM AUTHOR]

Microglia are involved in synaptic pruning both in development and in the mature CNS. In this study, we investigated whether microglia might further contribute to circuit plasticity by modulating neuronal recruitment from the neurogenic subventricular zone (SVZ) of the adult mouse striatum. We found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low expression of purinoceptors and lack of ATP-elicitable chemotaxis. Furthermore, the in vivo depletion of these microglia hampered the survival and migration of newly generated neuroblasts through the RMS to the olfactory bulb. SVZ and RMS microglia thus appear to comprise a functionally distinct class that is selectively adapted to the support and direction of neuronal integration into the olfactory circuitry. Therefore, this unique microglial subpopulation may serve as a novel target with which to modulate cellular addition from endogenous neural stem and progenitor cells of the adult brain. [ABSTRACT FROM AUTHOR]

The presence of a glymphatic pathway in the optic nerve and the theory that a dysfunctional glymphatic system may be involved in the pathogenesis of glaucoma were first proposed by Wostyn et al. (2015). The central nervous system (CNS) is largely devoid of functional lymphatic vessels, apart from within the meningeal lining (Louveau et al. 2015). Can we develop diagnostic tracers to study this pathway in a clinical setting and modulate transport to delay or prevent optic nerve diseases like glaucoma?. [Extracted from the article]

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α 2 -adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration. The brain clears itself of harmful metabolic waste through the glymphatic system to several egress routes, including the meningeal lymphatic vessels, and onward to cervical lymph nodes. In rodents, glymphatic flow declines in the awake state and increases with slow-wave activity in electroencephalography during non-rapid eye movement (NREM) sleep. Declining glymphatic function could be an underlying link between chronic sleep disturbance and neurodegeneration. Dexmedetomidine is a widely used and studied sedative agent that promotes NREM sleep in humans. Further, it has neuroprotective and anti-neuroinflammatory properties. In rodents, dexmedetomidine enhances the glymphatic clearance of intraparenchymal tracers from the rodent brain. Due to its mechanisms of action, safety, and ease of use through several noninvasive administration routes, dexmedetomidine should be studied as a self-administered sedative-hypnotic drug in outpatient care. It may be the best available sedative glymphatic enhancer and may prove to attenuate neurodegeneration in long-term use. [ABSTRACT FROM AUTHOR]

The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation. [ABSTRACT FROM AUTHOR]

Classical migraine patients can experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and trigeminal cells. After CSD, ~11% of the CSF proteome is altered, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion. CSF collected from animals exposed to CSD activates trigeminal neurons in naïve mice in part by CSF-borne calcitonin gene-related peptide (CGRP). We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache. [ABSTRACT FROM AUTHOR]

The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within the central nervous system (CNS). Imaging studies, as well as manipulations of fluid transport, point to a key role of the glymphatic–lymphatic system in clearance of amyloid-β and other proteins. As such, the glymphatic–lymphatic system represents a new target in combating neurodegenerative diseases. Not unexpectedly, introduction of a new plumbing system in the brain has stirred controversies. This opinion article will highlight what we know about the brain's fluid transport systems, where experimental data are lacking, and what is still debated. Several global models of brain fluid transport have been proposed. When assessing these models, it is imperative that they are based on observations in live animals. Cerebrospinal fluid (CSF) tracer distribution in histological sections mostly reflects nonphysiological events triggered after death. The literature suggests that diffusion and convective flow both contribute to clearance of CNS solutes. Experiments that are aimed at defining the relative contribution of diffusion versus convection are difficult to interpret because minor changes in physiological variables, such as body posture or respiratory rate, can significantly affect both pathways. Invasive procedures, such as tracer injection, will primarily suppress convective flow. The glymphatic system drives CSF into the brain along periarterial spaces and interstitial fluid (ISF) out along perivenous spaces. Aquaporin-4 (AQP4) water channels, densely expressed at the vascular endfeet of astrocytes, facilitate glymphatic transport, based on all studies on this topic (with one exception). Glymphatic–lymphatic efflux of amyloid-β contributes to diurnal variations in amyloid-β concentration in murine Alzheimer's disease models and represents a potential therapeutic target for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111 In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra- cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs. [Display omitted] • Brain access of intrathecally administered nanoparticles has been considered sparse. • Glymphatic-assisted CNS drug delivery has emerged as a new CNS drug delivery system. • We studied the brain distribution of 111In-labelled small gold nanoparticles (AuNPs). • Systemic hypertonic solution markedly increased brainwide AuNP delivery. • MRI of Gd-AuNPs visualizes their periarterial flow towards deep brain structures. [ABSTRACT FROM AUTHOR]

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport. [ABSTRACT FROM AUTHOR]

Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brain-barrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used α 2 -adrenergic agonist dexmedetomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics. Unlabelled Image • The glymphatic system drives cerebrospinal fluid influx into brain tissue. • Glymphatic flow is increased by drugs that decrease brain noradrenergic tone. • Dexmedetomidine is a clinically used α 2 -adrenergic agonist sedative. • Dexmedetomidine increases the brain delivery of intrathecally administered drugs. • Glymphatic flow can be manipulated to enhance the CNS delivery of intrathecal therapeutics. [ABSTRACT FROM AUTHOR]

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. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems. [ABSTRACT FROM AUTHOR]