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1.
PLoS Biol ; 18(5): e3000623, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369477

RESUMO

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.

2.
Prog Neurobiol ; : 101802, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32413398

RESUMO

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+, Ca2+ and Mg2+) 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.

3.
Nat Rev Nephrol ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235904

RESUMO

Cognitive impairment is an increasingly recognized major cause of chronic disability and is commonly found in patients with chronic kidney disease (CKD). Knowledge of the relationship between kidney dysfunction and impaired cognition may improve our understanding of other forms of cognitive dysfunction. Patients with CKD are at an increased risk (compared with the general population) of both dementia and its prodrome, mild cognitive impairment (MCI), which are characterized by deficits in executive functions, memory and attention. Brain imaging in patients with CKD has revealed damage to white matter in the prefrontal cortex and, in animal models, in the subcortical monoaminergic and cholinergic systems, accompanied by widespread macrovascular and microvascular damage. Unfortunately, current interventions that target cardiovascular risk factors (such as anti-hypertensive drugs, anti-platelet agents and statins) seem to have little or no effect on CKD-associated MCI, suggesting that the accumulation of uraemic neurotoxins may be more important than disturbed haemodynamic factors or lipid metabolism in MCI pathogenesis. Experimental models show that the brain monoaminergic system is susceptible to uraemic neurotoxins and that this system is responsible for the altered sleep pattern commonly observed in patients with CKD. Neural progenitor cells and the glymphatic system, which are important in Alzheimer disease pathogenesis, may also be involved in CKD-associated MCI. More detailed study of CKD-associated MCI is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention, and whether there may be novel approaches and potential therapies with wider application to this and other forms of cognitive decline.

4.
Sci Transl Med ; 12(536)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32213628

RESUMO

Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified an ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve in rodents. ß-amyloid (Aß) was cleared from the retina and vitreous via a pathway dependent on glial water channel aquaporin-4 (AQP4) and driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal Aß was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced efflux, whereas atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, Aß leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The results suggest that, in rodents, the removal of fluid and metabolites from the intraocular space occurs through a glymphatic pathway that might be impaired in glaucoma.

5.
Nat Rev Neurol ; 16(5): 285-296, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32152460

RESUMO

Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation - driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways - contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia-lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.

6.
Science ; 367(6483)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32001524

RESUMO

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies.


Assuntos
Edema Encefálico/líquido cefalorraquidiano , Edema Encefálico/etiologia , Sistema Glinfático/fisiopatologia , Acidente Vascular Cerebral/líquido cefalorraquidiano , Acidente Vascular Cerebral/complicações , Animais , Aquaporina 5/metabolismo , Edema Encefálico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/diagnóstico por imagem , Vasoconstrição
8.
Nat Rev Neurol ; 16(3): 137-153, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32094487

RESUMO

Perivascular spaces include a variety of passageways around arterioles, capillaries and venules in the brain, along which a range of substances can move. Although perivascular spaces were first identified over 150 years ago, they have come to prominence recently owing to advances in knowledge of their roles in clearance of interstitial fluid and waste from the brain, particularly during sleep, and in the pathogenesis of small vessel disease, Alzheimer disease and other neurodegenerative and inflammatory disorders. Experimental advances have facilitated in vivo studies of perivascular space function in intact rodent models during wakefulness and sleep, and MRI in humans has enabled perivascular space morphology to be related to cognitive function, vascular risk factors, vascular and neurodegenerative brain lesions, sleep patterns and cerebral haemodynamics. Many questions about perivascular spaces remain, but what is now clear is that normal perivascular space function is important for maintaining brain health. Here, we review perivascular space anatomy, physiology and pathology, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.


Assuntos
Encefalopatias , Sistema Glinfático/anatomia & histologia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/fisiologia , Animais , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Encefalopatias/fisiopatologia , Humanos
9.
Sci Rep ; 10(1): 1990, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029859

RESUMO

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD.

10.
Fluids Barriers CNS ; 17(1): 15, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046744

RESUMO

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.

11.
J Neurosci ; 40(11): 2371-2380, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047056

RESUMO

Chronic electroencephalography (EEG) is a widely used tool for monitoring cortical electrical activity in experimental animals. Although chronic implants allow for high-quality, long-term recordings in preclinical studies, the electrodes are foreign objects and might therefore be expected to induce a local inflammatory response. We here analyzed the effects of chronic cranial electrode implantation on glymphatic fluid transport and in provoking structural changes in the meninges and cerebral cortex of male and female mice. Immunohistochemical analysis of brain tissue and dura revealed reactive gliosis in the cortex underlying the electrodes and extensive meningeal lymphangiogenesis in the surrounding dura. Meningeal lymphangiogenesis was also evident in mice prepared with the commonly used chronic cranial window. Glymphatic influx of a CSF tracer was significantly enhanced at 30 d postsurgery in both awake and ketamine-xylazine anesthetized mice with electrodes, supporting the concept that glymphatic influx and intracranial lymphatic drainage are interconnected. Altogether, the experimental results provide clear evidence that chronic implantation of EEG electrodes is associated with significant changes in the brain's fluid transport system. Future studies involving EEG recordings and chronic cranial windows must consider the physiological consequences of cranial implants, which include glial scarring, meningeal lymphangiogenesis, and increased glymphatic activity.SIGNIFICANCE STATEMENT This study shows that implantation of extradural electrodes provokes meningeal lymphangiogenesis, enhanced glymphatic influx of CSF, and reactive gliosis. The analysis based on CSF tracer injection in combination with immunohistochemistry showed that chronically implanted electroencephalography electrodes were surrounded by lymphatic sprouts originating from lymphatic vasculature along the dural sinuses and the middle meningeal artery. Likewise, chronic cranial windows provoked lymphatic sprouting. Tracer influx assessed in coronal slices was increased in agreement with previous reports identifying a close association between glymphatic activity and the meningeal lymphatic vasculature. Lymphangiogenesis in the meninges and altered glymphatic fluid transport after electrode implantation have not previously been described and adds new insights to the foreign body response of the CNS.

12.
Trends Mol Med ; 26(3): 285-295, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31959516

RESUMO

Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-ß (Aß) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia-lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.

13.
Neurochem Res ; 45(1): 100-108, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31254249

RESUMO

Astrocytes are highly dynamic cells that modulate synaptic transmission within a temporal domain of seconds to minutes in physiological contexts such as Long-Term Potentiation (LTP) and Heterosynaptic Depression (HSD). Recent studies have revealed that astrocytes also modulate a faster form of synaptic activity (milliseconds to seconds) known as Transient Heterosynaptic Depression (tHSD). However, the mechanism underlying astrocytic modulation of tHSD is not fully understood. Are the traditional gliotransmitters ATP or glutamate released via hemichannels/vesicles or are other, yet, unexplored pathways involved? Using various approaches to manipulate astrocytes, including the Krebs cycle inhibitor fluoroacetate, connexin 43/30 double knockout mice (hemichannels), and inositol triphosphate type-2 receptor knockout mice, we confirmed early reports demonstrating that astrocytes are critical for tHSD. We also confirmed the importance of group II metabotropic glutamate receptors (mGluRs) in astrocytic modulation of tHSD using a group II agonist. Using dominant negative SNARE mice, which have disrupted glial vesicle function, we also found that vesicular release of gliotransmitters and activation of adenosine A1 receptors are not required for tHSD. As astrocytes can release lipids upon receptor stimulation, we asked if astrocyte-derived endocannabinoids are involved in tHSD. Interestingly, a cannabinoid receptor 1 (CB1R) antagonist blocked and an inhibitor of the endogenous endocannabinoid 2-arachidonyl glycerol (2-AG) degradation potentiates tHSD in hippocampal slices. Taken together, this study provides the first evidence for group II mGluR-mediated astrocytic endocannabinoids in transiently suppressing presynaptic neurotransmitter release associated with the phenomenon of tHSD.

14.
Lancet Psychiatry ; 7(3): 272-281, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31704113

RESUMO

The cellular neurobiology of schizophrenia remains poorly understood. We discuss neuroimaging studies, pathological findings, and experimental work supporting the idea that glial cells might contribute to the development of schizophrenia. Experimental studies suggest that abnormalities in the differentiation competence of glial progenitor cells lead to failure in the morphological and functional maturation of oligodendrocytes and astrocytes. We propose that immune activation of microglial cells during development, superimposed upon genetic risk factors, could contribute to defective differentiation competence of glial progenitor cells. The resulting hypomyelination and disrupted white matter integrity might contribute to transmission desynchronisation and dysconnectivity, whereas the failure of astrocytic differentiation results in abnormal glial coverage and support of synapses. The delayed and deficient maturation of astrocytes might, in parallel, lead to disruption of glutamatergic, potassium, and neuromodulatory homoeostasis, resulting in dysregulated synaptic transmission. By highlighting a role for glial cells in schizophrenia, these studies potentially point to new mechanisms for disease modification.

15.
Adv Neurobiol ; 23: 269-309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667812

RESUMO

A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is critical to qualify the role of glycogen in the brain. These molecular and metabolic features are under the control of neuronal activity through the interdependent action of neuromodulatory tone, ionic homeostasis and availability of metabolic substrates, all variables that concur to define the state of the system. In this chapter, we briefly describe how glycogen responds to selected behavioral, nutritional, environmental, hormonal, developmental and pathological conditions. We argue that interpreting glycogen metabolism through the lens of brain state is an effective approach to establish the relevance of energetics in connecting molecular and cellular neurophysiology to behavior.


Assuntos
Encéfalo/metabolismo , Glicogênio/metabolismo , Encéfalo/citologia , Encéfalo/patologia , Metabolismo Energético , Glicogênio/química , Neurônios/metabolismo
16.
Nat Rev Neurosci ; 20(11): 667-685, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31537912

RESUMO

Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte 'gliopathy'. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal-glial and glial-glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

17.
J Vis Exp ; (149)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31403617

RESUMO

Cerebrospinal fluid (CSF) flow in rodents has largely been studied using ex vivo quantification of tracers. Techniques such as two-photon microscopy and magnetic resonance imaging (MRI) have enabled in vivo quantification of CSF flow but they are limited by reduced imaging volumes and low spatial resolution, respectively. Recent work has found that CSF enters the brain parenchyma through a network of perivascular spaces surrounding the pial and penetrating arteries of the rodent cortex. This perivascular entry of CSF is a primary driver of the glymphatic system, a pathway implicated in the clearance of toxic metabolic solutes (e.g., amyloid-ß). Here, we illustrate a new macroscopic imaging technique that allows real-time, mesoscopic imaging of fluorescent CSF tracers through the intact skull of live mice. This minimally-invasive method facilitates a multitude of experimental designs and enables single or repeated testing of CSF dynamics. Macroscopes have high spatial and temporal resolution and their large gantry and working distance allow for imaging while performing tasks on behavioral devices. This imaging approach has been validated using two-photon imaging and fluorescence measurements obtained from this technique strongly correlate with ex vivo fluorescence and quantification of radio-labeled tracers. In this protocol, we describe how transcranial macroscopic imaging can be used to evaluate glymphatic transport in live mice, offering an accessible alternative to more costly imaging modalities.

18.
Cell Rep ; 28(5): 1182-1194.e4, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365863

RESUMO

Brain state fluctuations modulate sensory processing, but the factors governing state-dependent neural activity remain unclear. Here, we tracked the dynamics of cortical extracellular K+ concentrations ([K+]o) during awake state transitions and manipulated [K+]o in slices, during visual processing, and during skilled motor execution. When mice transitioned from quiescence to locomotion, [K+]o increased by 0.6-1.0 mM in all cortical areas analyzed, and this preceded locomotion by 1 s. Emulating the state-dependent [K+]o increase in cortical slices caused neuronal depolarization and enhanced input-output transformation. In vivo, locomotion increased the gain of visually evoked responses in layer 2/3 of visual cortex; this effect was recreated by imposing a [K+]o increase. Elevating [K+]o in the motor cortex increased movement-induced neuronal spiking in layer 5 and improved motor performance. Thus, [K+]o increases in a cortex-wide state-dependent manner, and this [K+]o increase affects both sensory and motor processing through the dynamic modulation of neural activity.

19.
Theranostics ; 9(15): 4474-4493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285774

RESUMO

Rational: Myelin loss is a characteristic feature of both ischemic white matter disease and its associated vascular dementia, and is a hallmark of chronic cerebral hypoperfusion due to carotid artery stenosis. Yet the cellular mechanisms involved in ischemic dysmyelination are not well-understood, and no effective treatment has emerged to prevent or slow hypoperfusion-related demyelination. In a study employing the bilateral common carotid artery stenosis (BCAS) mouse model, we found reduced cerebral blood flow velocity and arteriolar pulsatility, and confirmed that prolonged BCAS provoked myelin disruption. These pathological features were associated with marked cognitive decline, in the absence of evident damage to axons. Methods: To assess the role of astroglial communication in BCAS-associated demyelination, we investigated the effect of deleting or inhibiting connexin 43 (Cx43), a constituent of astroglial gap junctions and hemichannels. Results: Genetic deletion and pharmacological inhibition of gap junctions both protected myelin integrity and rescued cognitive decline in the BCAS-treated mice. Gap junction inhibition also suppressed the transient increase in extracellular glutamate observed in the callosal white matter of wild-type mice exposed to BCAS. Conclusion: These findings suggest that astrocytic Cx43 may be a viable target for attenuating the demyelination and cognitive decline associated with chronic cerebral hypoperfusion.

20.
Biomed Opt Express ; 10(7): 3699-3718, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31360610

RESUMO

In dynamic optical coherence elastography (OCE), surface acoustic waves are the predominant perturbations. They constrain the quantification of elastic modulus to the direction of wave propagation only along the surface of tissues, and disregard elasticity gradients along depth. Longitudinal shear waves (LSW), on the other hand, can be generated at the surface of the tissue and propagate through depth with desirable properties for OCE: (1) LSW travel at the shear wave speed and can discriminate elasticity gradients along depth, and (2) the displacement of LSW is longitudinally polarized along the direction of propagation; therefore, it can be measured by a phase-sensitive optical coherence tomography system. In this study, we explore the capabilities of LSW generated by a circular glass plate in contact with a sample using numerical simulations and tissue-mimicking phantom experiments. Results demonstrate the potential of LSW in detecting an elasticity gradient along axial and lateral directions simultaneously. Finally, LSW are used for the elastography of ex vivo mouse brain and demonstrate important implications in in vivo and in situ measurements of local elasticity changes in brain and how they might correlate with the onset and progression of degenerative brain diseases.

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