scholarly journals Reduction of neuronal activity mediated by blood-vessel regression in the brain

2020 ◽  
Author(s):  
Xiaofei Gao ◽  
Jun-Liszt Li ◽  
Xingjun Chen ◽  
Bo Ci ◽  
Fei Chen ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Neuronal Activity ◽  
Leukocyte Adhesion ◽  
Adult Brain ◽  
Brain Vasculature ◽  
Vessel Regression ◽  
Blood Flow Occlusion ◽  
Human Brains ◽  
The Brain

SummaryThe brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

scholarly journals Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Angiogenesis ◽  
2021 ◽  
Author(s):  
Delphine M. Lees ◽  
Louise E. Reynolds ◽  
Ana Rita Pedrosa ◽  
Marina Roy-Luzarraga ◽  
Kairbaan M. Hodivala-Dilke
Keyword(s):  
Blood Vessel ◽  
Tumour Growth ◽  
Vascular Endothelial Cell ◽  
Vessel Density ◽  
In Vivo Studies ◽  
Blood Vessel Density ◽  
Tumour Vessel ◽  
Vessel Regression ◽  
Tumour Blood

AbstractFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

scholarly journals Microglia motility depends on neuronal activity and promotes structural plasticity in the hippocampus

2019 ◽  
Author(s):  
Felix C. Nebeling ◽  
Stefanie Poll ◽  
Lena C. Schmid ◽  
Manuel Mittag ◽  
Julia Steffen ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Dendritic Spines ◽  
Synapse Formation ◽  
Brain Parenchyma ◽  
Two Photon ◽  
Contact Rates ◽  
Health And Disease ◽  
The Impact ◽  
The Brain

AbstractMicroglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

Biophysical basis of brain activity: implications for neuroimaging

2002 ◽  
Vol 35 (3) ◽  
pp. 287-325 ◽  
Author(s):  
Robert G. Shulman ◽  
Fahmeed Hyder ◽  
Douglas L. Rothman
Keyword(s):  
Energy Consumption ◽  
Magnetic Resonance ◽  
Neuronal Activity ◽  
Glucose Oxidation ◽  
Activity Level ◽  
Quantitative Relation ◽  
Cerebral Function ◽  
Level Of Activity ◽  
The Brain

1. Summary 2882. Introduction 2883. Relationship between neuroenergetics and neurotransmitter flux 2944. A model of coupling between neuroenergetics and neurotransmission 2965. Relationship between neuroenergetics and neural spiking frequency 2976. Comparison with previous electrophysiological and fMRI measurements 2987. Contributions of non-oxidative energetics to a primarily oxidative brain 2998. Possible explanation for non-oxidative energetics contributions 3009. A model of total neuronal activity to support cerebral function 30210. Implications for interpretation of fMRI studies 30511. The restless brain 30612. Acknowledgements 31013. Appendix A. CMRO2by13C-MRS 31014. Appendix B.Vcycand test of model 31315. Appendix C. CMRO2by calibrated BOLD 31616. Appendix D. Comparison of spiking activity of a neuronal ensemble with CMRO231817. References 320In vivo13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively assessed rates of glutamate–glutamine cycle (Vcyc) and glucose oxidation (CMRGlc(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in vivo13C-MRS results demonstrate that glutamate recycling is a major metabolic pathway, inseparable from its actions of neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain, Vcyc and CMRGlc(ox) are stoichiometrically related, where more than two thirds of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain measured at rest and its quantitative relation to neurotransmission reflects a sizeable activity level for the resting brain. The high activity of the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral function that leads to reinterpreting functional imaging data because the large baseline signal is commonly discarded in cognitive neuroscience paradigms. Changes in energy consumption (ΔCMRO2%) can also be obtained from magnetic resonance imaging (MRI) experiments, using the blood oxygen level- dependent (BOLD) image contrast, provided that all the separate parameters contributing to the functional MRI (fMRI) signal are measured. The BOLD-derived ΔCMRO2% when compared with alterations in neuronal spiking rate (Δν%) during sensory stimulation in the rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence fMRI when calibrated so as to provide ΔCMRO2% can provide high spatial resolution evaluation of neuronal activity. Our studies of quantitative measurements of changes in neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary amount of activity in a localized region, rather a total level of activity is required where the increment is inversely related to the level of activity in the non-stimulated condition. These biophysical experiments have established relationships between energy consumption and neuronal activity that provide novel insights into the nature of brain function and the interpretation of fMRI data.

scholarly journals Ackr3-Venus knock-in mouse lights up brain vasculature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Aliza T. Ehrlich ◽  
Meriem Semache ◽  
Pierre Couvineau ◽  
Stefan Wojcik ◽  
Hiroyuki Kobayashi ◽  
...  
Keyword(s):  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Adult Brain ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Membrane Expression ◽  
Hek 293 ◽  
Brain Vasculature ◽  
Intact Gene ◽  
The Brain

AbstractThe atypical chemokine receptor 3, ACKR3, is a G protein-coupled receptor, which does not couple to G proteins but recruits βarrestins. At present, ACKR3 is considered a target for cancer and cardiovascular disorders, but less is known about the potential of ACKR3 as a target for brain disease. Further, mouse lines have been created to identify cells expressing the receptor, but there is no tool to visualize and study the receptor itself under physiological conditions. Here, we engineered a knock-in (KI) mouse expressing a functional ACKR3-Venus fusion protein to directly detect the receptor, particularly in the adult brain. In HEK-293 cells, native and fused receptors showed similar membrane expression, ligand induced trafficking and signaling profiles, indicating that the Venus fusion does not alter receptor signaling. We also found that ACKR3-Venus enables direct real-time monitoring of receptor trafficking using resonance energy transfer. In ACKR3-Venus knock-in mice, we found normal ACKR3 mRNA levels in the brain, suggesting intact gene transcription. We fully mapped receptor expression across 14 peripheral organs and 112 brain areas and found that ACKR3 is primarily localized to the vasculature in these tissues. In the periphery, receptor distribution aligns with previous reports. In the brain there is notable ACKR3 expression in endothelial vascular cells, hippocampal GABAergic interneurons and neuroblast neighboring cells. In conclusion, we have generated Ackr3-Venus knock-in mice with a traceable ACKR3 receptor, which will be a useful tool to the research community for interrogations about ACKR3 biology and related diseases.

scholarly journals Protein lactylation induced by neural excitation

2021 ◽  
Author(s):  
Hideo Hagihara ◽  
Hirotaka Shoji ◽  
Hikari Otabi ◽  
Atsushi Toyoda ◽  
Kaoru Katoh ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Monocarboxylate Transporter ◽  
Brain Cells ◽  
Post Translational Modification ◽  
High Potassium ◽  
Neural Excitation ◽  
Lactate Levels ◽  
The Brain ◽  
Prefrontal Cortices

AbstractLactate is known to have diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions, such as learning and memory and regulation of mood. Recently, a novel post-translational modification called lysine lactylation has been found in histone H3 of mouse macrophages, and the lactylation levels paralleled the intracellular lactate levels1. However, it is unknown whether lysine lactylation occurs in brain cells, and if it does, whether lactylation is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that lysine lactylation in brain cells is regulated by systemic changes in lactate levels, neural excitation, and behaviorally relevant stimuli. Lysine lactylation levels were increased by lactate treatment and by high-potassium-induced depolarization in cultured primary neurons; these increases were attenuated by pharmacological inhibition of monocarboxylate transporter 2 and lactate dehydrogenase, respectively, suggesting that both cell-autonomous and non-cell-autonomous neuronal mechanisms are involved in overall lysine lactylation. In vivo, electroconvulsive stimulation increased lysine lactylation levels in the prefrontal cortices of mice, and its levels were positively correlated with the expression levels of the neuronal activity marker c-Fos on an individual cell basis. In the social defeat stress model of depression in which brain lactate levels increase, lactylation levels were increased in the prefrontal cortices of the defeated mice, which was accompanied by increased c-Fos expression, decreased social behaviors, and increased anxiety-like behaviors, suggesting that stress-induced neuronal excitation may induce lysine lactylation, thereby affecting mood-related behaviors. Further, we identified 63 candidate lysine-lactylated proteins in the mouse cortex and found that lactylation levels in histone H1 increased in response to defeat stress. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.

scholarly journals Brain Endothelial Cell TRPA1 Channels Initiate Neurovascular Coupling

2020 ◽  
Author(s):  
Pratish Thakore ◽  
Michael G. Alvarado ◽  
Sher Ali ◽  
Amreen Mughal ◽  
Paulo W. Pires ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Neuronal Activity ◽  
Transient Receptor Potential ◽  
Neurovascular Coupling ◽  
Laser Scanning Microscopy ◽  
K Channel ◽  
Transitional Region ◽  
Capillary Endothelial Cells ◽  
The Brain

Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand.

scholarly journals In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

2020 ◽  
Author(s):  
Monique S. Mendes ◽  
Jason Atlas ◽  
Zachary Brehm ◽  
Antonio Ladron-de-Guevara ◽  
Matthew N. McCall ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Visual Cortex ◽  
Adult Brain ◽  
Self Renewal ◽  
Two Photon ◽  
And Migration ◽  
The Mathematical Model ◽  
Kinetics Of ◽  
The Brain

AbstractMicroglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.Graphical Abstract(a) Microglial dynamics during control condition. Cartoon depiction of the heterogenous microglia in the visual cortex equally spaced. (b) During the early stages of repopulation, microglia are irregularly spaced and sparse. (c) During the later stages of repopulation, the number of microglia and the spatial distribution return to baseline. (d-f) We then created and ran a mathematical model that sampled the number of microglia, (d) the persistent doublets, (e) the rapid divisions of microglia and (f) the secondary divisions of microglia during the peak of repopulation day 2-day 3. The mathematical model suggested that residual microglia can account for the rapid repopulation we observed in vivo.

Abstract 82: In Vivo Memri Reveals Persistent Activation of the Pvn by an Acute Systemic Angiotensin Ii Injection

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Jasenka Zubcevic ◽  
Pablo D Perez ◽  
Jessica Marulanda Carvajal ◽  
Mohan K Raizada ◽  
Marcelo Febo
Keyword(s):  
Neuronal Activity ◽  
Spontaneously Hypertensive Rat ◽  
Pressor Response ◽  
Neuronal Response ◽  
Neuronal Activation ◽  
Brain Areas ◽  
Neurogenic Hypertension ◽  
Wistar Kyoto ◽  
The Brain

Introduction: An overactive brain renin-angiotensin system is a major factor in the establishment of neurogenic hypertension in the spontaneously hypertensive rat (SHR). However, there is no concrete evidence to indicate that this is associated with enhanced neuronal activity in the brain. The objective here was to use the MRI to establish the effect of ANGII on neuronal activity in the autonomic brain areas. We propose that a single ANGII injection will cause a long-lasting neuronal response in the autonomic brain areas, which will be exaggerated in the SHR. Methods: In vivo basal and ANGII-evoked neuronal activity was measured in the Wistar-Kyoto (WKY) rat and the SHR using manganese-enhanced MRI (MEMRI) at 4.7Tesla. Rats were treated with manganese chloride (MnCl 2 30 mM solution, i.p .;16-20 hrs prior to the MRI), which labels active neurons. T 1 -weighted images were obtained 16-20 hrs after a single ANGII injection (0.32μg/kg i.p.). Coronal slice scans (caudally from end of the cerebellum towards the hypothalamus) were processed using itkSNAP, and data analyzed for normalized signal intensity. Results: Acute ANGII injection caused an immediate pressor response in the WKY (ΔSBP=∼20mmHg), normalizing within 2 hours. Despite this, ANGII evoked a persistent PVN neuronal activation, which was elevated by 22±4% in the WKY, and by 187±45% in the PVN of SHR. As a result, there was a ∼8.5fold increase in the ANGII-dependent neuronal activity in the PVN of SHR compared to WKY. Furthermore, there was a ∼2.5fold decrease in the NTS neuronal activity in the SHR compared to WKY. Conclusion: The present study shows for the first time the correlation between ANGII and autonomic neuronal activation. Even a single systemic ANGII injection results in a lasting effect on the brain. This is particularly apparent in the SHR, which exhibited an exaggerated neuronal response to the ANGII stimulus, reflected in the elevated PVN neuronal activation corresponding to the enhanced sympathetic drive, and in the depressed NTS activation corresponding to the dysfunction in the barorereflex processing. Thus, repeated pro-hypertensive stimuli in the autonomic brain areas may lead to pre-sympathetic neuronal plasticity, resulting in heightened sympathetic drive and hypertension.

scholarly journals Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

2020 ◽  
Vol 21 (8) ◽  
pp. 2743 ◽  
Author(s):  
Marco Sancandi ◽  
Pinar Uysal-Onganer ◽  
Igor Kraev ◽  
Audrey Mercer ◽  
Sigrun Lange
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Lupus Erythematosus ◽  
Biomarker Discovery ◽  
Alcoholic Fatty Liver ◽  
Brain Vasculature ◽  
Micro Rnas ◽  
The Brain

The identification of biomarkers for early diagnosis of Parkinson’s disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to “Alzheimer’s disease”, “PD”, “Huntington’s disease”, “prion diseases”, as well as for “oxidative phosphorylation”, “thermogenesis”, “metabolic pathways”, “Staphylococcus aureus infection”, gap junction, “platelet activation”, “apelin signalling”, “retrograde endocannabinoid signalling”, “systemic lupus erythematosus”, and “non-alcoholic fatty liver disease”. Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD.

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