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CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis
Here, the authors demonstrate that CXCL5 expression is increased in ankle joints of gouty arthritis model mice. CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and joint inflammation.
- Chengyu Yin
- , Boyu Liu
- & Boyi Liu
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Article
| Open Access
Distinct neurochemical influences on fMRI response polarity in the striatum
The relationship between striatal vascular and neural activity is not fully understood. Here the authors found neuronal activity inadequately explains striatal hemodynamic polarity, challenging classic fMRI interpretations.
- Domenic H. Cerri
- , Daniel L. Albaugh
- & Yen-Yu Ian Shih
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Article
| Open Access
SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability
Pubertal timing in mammals depends on the function of GnRH neurons that innervate the median eminence (ME) of the hypothalamus. Here, the authors show that Semaphorin 6A regulates GnRH innervation and puberty onset by tuning vascular permeability at the ME.
- Antonella Lettieri
- , Roberto Oleari
- & Anna Cariboni
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| Open Access
Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines
Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here the authors show studies of transgenic chemogenetic mouse lines that develop sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress.
- Shambhu Yadav
- , Markus Waldeck-Weiermair
- & Thomas Michel
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| Open Access
Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy
Brain microvascular dysfunction occurs in Alzheimer’s disease and other taupathies. Here the authors show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy, and that it contributes to vascular deficits in these mice.
- Stacy A. Hussong
- , Andy Q. Banh
- & Veronica Galvan
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| Open Access
Subcellular analysis of blood-brain barrier function by micro-impalement of vessels in acute brain slices
The blood-brain barrier (BBB) tightly and dynamically regulates exchange with the brain. Here, the authors report a brain slice approach to study the native BBB in a highly controlled manner by combining intravascular perfusion and multiphoton microscopy.
- Amira Sayed Hanafy
- , Pia Steinlein
- & Dirk Dietrich
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Astrocytes amplify neurovascular coupling to sustained activation of neocortex in awake mice
Neuronal activity increases local cerebral blood flow (CBF) to satisfy metabolic demand, yet the role of astrocytes in this phenomenon is controversial. Here, the authors show that astrocytes amplify CBF only when neuronal activity is sustained.
- Adam Institoris
- , Milène Vandal
- & Grant R. Gordon
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Endothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke
Damaged brains try to repair themselves by producing neurons in areas where neurogenesis does not normally occur. Here, the authors show that brain endothelial cells provide microvesicle-encased signals that convert parenchymal astrocytes into neural progenitors, thus improving outcomes after stroke.
- Wenlu Li
- , Emiri T. Mandeville
- & Eng H. Lo
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Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin
Inflammation of brain endothelial cells is seen in neurodegenerative conditions and in aging. Here the authors examine the role of astrocytes in blood brain barrier function using an iPSC-derived cell co-culture model.
- Hyosung Kim
- , Kun Leng
- & Ethan S. Lippmann
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Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
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Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease
The precise boundaries and flow compartments of perivascular spaces in the brain are incompletely understood. Here the authors show that pia is perforated and permissive to CSF flow, forming three types of perivascular spaces that remodel with age, with an abnormal type arising in Alzheimer’s disease and correlating with β-amyloid burden and differential macrophage uptake.
- Humberto Mestre
- , Natasha Verma
- & Rupal I. Mehta
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Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age
Disruption of the blood brain barrier can occur in several diseases. Here the authors show that targeted ablation of astrocytes results in a plasticity mechanism in nearby cells to maintain cerebrovascular coverage, but that this mechanism is impaired in older animals.
- William A. Mills III
- , AnnaLin M. Woo
- & Harald Sontheimer
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Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes
Studies in animal models have visualized drainage of interstitial or cerebrospinal fluid via lymphatic vessels, but there is limited data on in humans. Here, the authors non-invasively visualize lymphatic structures in the human brain, including evidence of lymphatic flow from cranial nerves to cervical lymph nodes, and differences by age and sex, without use of contrast agents.
- Mehmet Sait Albayram
- , Garrett Smith
- & Onder Albayram
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| Open Access
Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption
Cellular models of organs have been used to investigate mechanisms of disease. Here the authors generate a human alpha synuclein-induced brain-chip model that recapitulates blood-brain barrier dysfunction, as a potential testing platform for novel therapeutics in Parkinson’s disease.
- Iosif Pediaditakis
- , Konstantia R. Kodella
- & Katia Karalis
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| Open Access
Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain
The first known portal system in the mammalian brain was identified in 1933. Here the authors describe a new portal system between the capillary beds of the Suprachiasmatic Nucleus master clock and a circumventricular organ, enabling humoral signals to reach targets without dilution in the systemic circulation.
- Yifan Yao
- , Alana B’nai Taub
- & Rae Silver
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Microglia have a grip on brain microvasculature
Microglia are brain resident immune cells with multiple functions. However, little is known about microglia-vascular interactions. In a recent paper published in Nature Communications, Bisht et al. identify a signalling mechanism that attracts and maintains microglia at the capillary wall. Moreover, they show that microglia regulate capillary vascular tone, playing a more significant role in blood flow regulation than previously thought.
- Kassandra Kisler
- , Angeliki Maria Nikolakopoulou
- & Berislav V. Zlokovic
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Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice
Microglia are involved in debris clearance and synaptic pruning, among other processes. However, their direct interaction with the brain vasculature is less clear. Here, the authors show that capillary-associated microglia (CAMs) regulate vascular tone via PANX1-P2RY12 signalling.
- Kanchan Bisht
- , Kenneth A. Okojie
- & Ukpong B. Eyo
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| Open Access
Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences
The hippocampus is particularly sensitive to hypoxia but it has been difficult to study blood flow in this region. Here the authors compare the neurovascular function of the hippocampus and cortex and in awake mice, and find differences associated with microvascular structure.
- K. Shaw
- , L. Bell
- & C. N. Hall
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Adaptive modulation of brain hemodynamics across stereotyped running episodes
Theta and gamma rhythms are essential to ensure timely communication between brain structures during locomotion. Here the authors investigate the association between cerebral blood flow and neural oscillations in freely behaving mice running a linear track.
- Antoine Bergel
- , Elodie Tiran
- & Ivan Cohen
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| Open Access
High-speed volumetric two-photon fluorescence imaging of neurovascular dynamics
Monitoring hemodynamics in the brain is important in understanding medical imaging data and mechanisms of disease. Here the authors use high-throughput two-photon microscopy with an axially-extended Bessel focus to measure vessel size and blood flow down to capillary scale in the awake mouse brain.
- Jiang Lan Fan
- , Jose A. Rivera
- & Na Ji
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Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.
- Ashley C. Bolte
- , Arun B. Dutta
- & John R. Lukens
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Precapillary sphincters maintain perfusion in the cerebral cortex
Precapillary sphincters are mural cells encircling an indentation of blood vessels where capillaries branch off from penetrating arterioles (PAs), but their existence and role in the brain is not fully understood. Here authors describe these structures at PAs in the cortex and show that they constrict during cortical spreading depolarization in mice.
- Søren Grubb
- , Changsi Cai
- & Martin Lauritzen
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| Open Access
Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow
The brain receives 20% of cardiac output, but in accord with the current knowledge lacks a specialized sensor of its own blood flow. Here, the authors show that brain astrocytes detect drops in perfusion and trigger compensatory increases in arterial pressure and heart rate to preserve brain blood flow and oxygen delivery.
- Nephtali Marina
- , Isabel N. Christie
- & Alexander V. Gourine
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Cerebral oxygenation during locomotion is modulated by respiration
Understanding mechanisms of cerebral oxygen regulation is critical for healthy brain function. Here the authors show that respiration is a key modulator of cerebral oxygenation, which will be helpful in better resolving neurally-generated functional brain imaging signals, such as BOLD fMRI.
- Qingguang Zhang
- , Morgane Roche
- & Patrick J. Drew
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Mapping optogenetically-driven single-vessel fMRI with concurrent neuronal calcium recordings in the rat hippocampus
Detailed characterization of large-scale hemodynamic responses linked to specific neural activity remains to be elucidated at the single-vessel level across the subcentimeter scale hippocampal vasculature in vivo. Here, authors use a novel multi-modal fMRI platform to characterize distinct spatiotemporal patterns of hippocampal hemodynamic responses that were correlated to the optogenetically evoked Ca2+ events and to further demonstrate the significantly reduced neurovascular coupling efficiency upon spreading depression-like Ca2+ events.
- Xuming Chen
- , Filip Sobczak
- & Xin Yu
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| Open Access
MRI-guided robotic arm drives optogenetic fMRI with concurrent Ca2+ recording
Fiber optic implantation in deep areas of the rodent’s brain for MRI combined with optogenetics is challenging. Here the authors use an MRI-guided robotic arm as the navigation method for accurate fiber optic placement and precise microinjection during multi-modal fMRI, optogenetics and calcium recordings.
- Yi Chen
- , Patricia Pais-Roldan
- & Xin Yu
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Characterization of the hemodynamic response function in white matter tracts for event-related fMRI
The hemodynamic response function (HRF) describes how changes in brain activity manifest as a transient signal (BOLD) that is detected by fMRI imaging. Here, the authors show that the HRF in white matter shows reduced magnitudes, delayed onsets, and prolonged initial dips compared to the grey matter HRF.
- Muwei Li
- , Allen T. Newton
- & John C. Gore
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| Open Access
Mesoscopic and microscopic imaging of sensory responses in the same animal
Neuronal activity leads to a local increase in blood flow and volume, a process termed hyperaemia. Here, the authors employ multiple imaging approaches of neuronal and vascular activity at varying resolution to delineate the spatiotemporal dynamics of neurovascular coupling evoked by odours in the olfactory bulb.
- Davide Boido
- , Ravi L. Rungta
- & Serge Charpak
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| Open Access
Correspondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain
The brain primarily uses glucose to generate energy, but the relationship of neuronal activity to glucose utilization is not necessarily a simple linear one. Here, the authors introduce relative power (rPWR) and relative cost (rCST) as new metrics to quantify how brain activity relates to glucose consumption.
- Ehsan Shokri-Kojori
- , Dardo Tomasi
- & Nora D. Volkow
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| Open Access
A miniature multi-contrast microscope for functional imaging in freely behaving animals
Measuring multiple neurophysiologic variables usually requires bulky benchtop optical systems and working with anesthetized animals. Here the authors present a miniature portable microscope for neurovascular imaging in awake rodents, combining fluorescence, intrinsic optical signals and laser speckle contrast.
- Janaka Senarathna
- , Hang Yu
- & Arvind P. Pathak
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| Open Access
Local hippocampal fast gamma rhythms precede brain-wide hyperemic patterns during spontaneous rodent REM sleep
Neural activity during REM sleep is similar to the waking state. Here, the authors measure blood volume with neurofunctional ultrasound imaging together with hippocampal neural activity during REM sleep and report that fast gamma oscillations are coupled to a brain-wide upregulation of vascular flow.
- Antoine Bergel
- , Thomas Deffieux
- & Ivan Cohen
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Article
| Open Access
Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension
Arterial pulsations are thought to drive CSF flow through perivascular spaces (PVSs), but this has never been quantitatively shown. Using particle tracking to quantify CSF flow velocities in PVSs of live mice, the authors show that flow speeds match the instantaneous speeds of the pulsing artery walls that form the inner boundaries of the PVSs.
- Humberto Mestre
- , Jeffrey Tithof
- & Douglas H. Kelley
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| Open Access
Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function
ApoE4 is a risk factor for small vessel disease, which can lead to cognitive impairment. Here the authors assess the microvasculature of the corpus callosum using 3-photon microscopy and find that mice expressing the ApoE4 allele are more susceptible than wild-type to white matter injury and cognitive impairment in a model of hypoperfusion-induced hypoxia.
- Kenzo Koizumi
- , Yorito Hattori
- & Costantino Iadecola
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| Open Access
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice
It is believed that the bulk of cerebrospinal fluid (CSF) drains through arachnoid projections from the subarachnoid space to the dural venous sinuses. Here the authors show that the major outflow pathway for CSF in mice are lymphatic vessels and that this drainage decreases as the mice age.
- Qiaoli Ma
- , Benjamin V. Ineichen
- & Steven T. Proulx
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| Open Access
Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease
Cerebrovascular changes and astrogliosis occur in Alzheimer’s disease (AD). Using an in vivo phage display technique, the authors identified a peptide that upon systematic administration, can home to brain endothelial cells and astrocytes in mouse models of AD at the early stages of the disease.
- Aman P. Mann
- , Pablo Scodeller
- & Erkki Ruoslahti
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| Open Access
Neurovascular EGFL7 regulates adult neurogenesis in the subventricular zone and thereby affects olfactory perception
The vascular stem cell niche regulates the proliferation and differentiation of neural stem cells (NSCs) in the adult subventricular zone. Here the authors identify EGFL7 as a neurovascular regulator of NSCsin vivo; EGFL7-knockout mice show reduced neurogenesis, and exhibit impaired olfactory perception and behaviour.
- Frank Bicker
- , Verica Vasic
- & Mirko H. H. Schmidt
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| Open Access
Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1
Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morlandet al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.
- Cecilie Morland
- , Krister A. Andersson
- & Linda H. Bergersen
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Article
| Open Access
Light controls cerebral blood flow in naive animals
Combination of optogenetics and BOLD fMRI is routinely used to map neuronal activity upon photostimulation. Here the authors show that light, shone at intensities used in optogenetic studies, dilates vessels and increases blood flow independently of exogenous light-sensitive proteins in the mouse brain.
- Ravi L Rungta
- , Bruno-Félix Osmanski
- & Serge Charpak
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Article
| Open Access
Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure
Cerebrovascular accumulation of Aβ is a common feature of Alzheimer’s disease, though it is unclear whether mutant vascular amyloid is capable of Aβ seeding. Here, the authors show microvascular amyloid seeds are capable of driving wild-type Aβ to assemble into distinctive anti-parallel fibrillary structures.
- Feng Xu
- , Ziao Fu
- & William E. Van Nostrand
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Article
| Open Access
A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication
Immune system participates in the development of high blood pressure. Here the authors show that cholinergic-sympathetic pathway mediated by the α7nAChR receptor and the activation of splenic T cells prime immunity during hypertension and that selective splenic denervation protects against the onset of hypertension in mice.
- Daniela Carnevale
- , Marialuisa Perrotta
- & Giuseppe Lembo
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Disruption of astrocyte–vascular coupling and the blood–brain barrier by invading glioma cells
Astrocytic endfeet maintain endothelial tight junctions that form the blood–brain barrier (BBB), which can be damaged by invading gliomas. Here, the authors show that this damage is due to the association of gliomas with existing vessels and the displacement of astrocytic endfeet.
- Stacey Watkins
- , Stefanie Robel
- & Harald Sontheimer
Cortex-wide transcranial localization microscopy with fluorescently labeled red blood cells