Biology subjects

Chaumeil, M. M.

Publications and source records attributed to Chaumeil, M. M..

6 recordsLinked to original sources

bioRxiv2023

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease

Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K+ (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2 by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD. One-sentence summaryPI3K inhibition rescues neurovascular coupling defects in cerebral small vessel disease.

neuroscience↗

bioRxiv2022

Defective Ca2+- dependent activation of TRPM4 channels contributes to age-related cerebral small vessel disease in Col4a1 mutant mice

Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of cerebral small vessel disease (cSVD), but the pathogenic mechanisms are largely unknown. Mice with a missense mutation in Col4a1 at amino acid 1344 (Col4a1+/G1344D) exhibited age-dependent intracerebral hemorrhage (ICH) and brain lesions. Here we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Further, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+ signaling. Treating Col4a1+/G1344D mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+ signaling, BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICH. We conclude that alterations in SR Ca2+ handling that impair membrane potential regulating ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone contributing to age-related cSVD in Col4a1+/G1344D mice. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/505186v3_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@11a8cb9org.highwire.dtl.DTLVardef@d00b8org.highwire.dtl.DTLVardef@1aa5b24org.highwire.dtl.DTLVardef@145a9c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2021

Evidence for glutamine synthetase function in mouse spinal cord oligodendrocytes

Glutamine synthetase (GS) is a key enzyme that metabolizes glutamate into glutamine. While GS is expressed by astrocytes of the central nervous system (CNS), expression in other glial lineages has been noted. Using a combination of reporter mice and cell typespecific markers, we show that GS is expressed in myelinating oligodendrocytes (OL) but not oligodendrocyte progenitor cells (OPC) of the mouse spinal cord abutting ventral horn motor neurons. To investigate the role of GS in mature OL, we used a conditional knockout (cKO) approach to selectively delete GS-encoding gene (Glul) in OL, which caused a significant decrease in glutamine levels on spinal cord extracts. We evaluated the effect on ventral spinal cord sensorimotor circuits and observed that GS cKO mice (CNP-cre+: Glulfl/fl) showed no differences in motor neuron numbers, size or axon density; OL differentiation and myelination in the ventral spinal cord at 1- and 6-months of age was normal. Interestingly, GS cKO mice showed an early and specific decrease in peak force while motor function remained otherwise unaffected. These findings provide evidence OL-encoded GS functions in spinal cord sensorimotor circuit. Main pointsO_LIGlutamine synthetase (GS) is highly expressed in oligodendrocytes (OL) of the mouse spinal cord. C_LIO_LIOL-specific GS loss of function causes transient decrease in peak force, but other substantial neurological dysfunction was not detected. C_LI

neuroscience↗

bioRxiv2021

Open Data Commons for Preclinical Traumatic Brain Injury Research: Empowering Data Sharing and Big Data Analytics

Traumatic brain injury (TBI) is a major unsolved public health problem worldwide with considerable preclinical research dedicated to recapitulating clinical TBI, deciphering the underlying pathophysiology, and developing therapeutics. However, the heterogeneity of clinical TBI and correspondingly in preclinical studies have made translation from bench to bedside difficult. Here, we present the potential of data sharing, data aggregation, and multivariate analytics to integrate heterogeneity and empower researchers. We introduce the Open Data Commons for Traumatic Brain Injury (ODC-TBI.org) as a user-centered web platform and cloudbased repository focused on preclinical TBI research that enables data citation with persistent identifiers, promotes data element harmonization, and follows FAIR data sharing principles. Importantly, the ODC-TBI implements data sharing at the level of individual subjects, thus enabling data reuse for granular big data analytics and data-hungry machine learning approaches. We provide use cases applying descriptive analytics and unsupervised machine learning on pooled ODC-TBI data. Descriptive statistics included subject-level data for 11 published papers (N = 1250 subjects) representing six distinct TBI models across mice and rats (implementing controlled cortical impact, closed head injury, fluid percussion injury, and CHIMERA TBI modalities). We performed principal component analysis (PCA) on cohorts of animals combined through the ODC-TBI to identify persistent inflammatory patterns across different experimental designs. Our workflow ultimately improved the sensitivity of our analyses in uncovering patterns of pro- vs anti-inflammation and oxidative stress without the multiple testing problems of univariate analyses. As the practice of open data becomes increasingly required by the scientific community, ODC-TBI provides a foundation that creates new scientific opportunities for researchers and their work, facilitates multi-dataset and multidimensional analytics, and drives collaboration across molecular and computational biologists to bridge preclinical research to the clinic.

neuroscience↗

bioRxiv2020

Non-invasive Differentiation of M1 and M2 Activation in Macrophages using Hyperpolarized 13C MRS of Pyruvate and DHA at 1.47 Tesla

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical pro-inflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to non-invasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses. Since M1/M2 activation patterns are associated with differential metabolic reprogramming, we hypothesized that hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS), an innovative metabolic imaging approach, could distinguish between macrophage activation states noninvasively. The metabolic conversions of HP [1-13C]pyruvate to HP [1-13C]lactate and HP [1-13C]dehydroascorbic acid to HP [1-13C]ascorbic acid were monitored in live M1 and M2 activated J774a.1 macrophages non-invasively by HP 13C MRS on a 1.47 Tesla NMR system. Our results show that both metabolic conversions were significantly increased in M1 macrophages compared to M2 and non-activated cells. Biochemical assays and high resolution 1H MRS were also performed to investigate the underlying changes in enzymatic activities and metabolite levels linked to M1/M2 activation. Altogether, our results demonstrate the potential of HP 13C MRS for monitoring macrophage activation states non-invasively.

biochemistry↗

bioRxiv2019

Imaging toxin-induced neuroinflammation in mice using hyperpolarized 13C magnetic resonance spectroscopy

Lipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessing in vivo neuroinflammation and its modulation following therapy remains challenging, and new non-invasive methods allowing for longitudinal monitoring would be greatly valuable. Hyperpolarized (HP) 13C magnetic resonance spectroscopy (MRS) is a promising technique for assessing in vivo metabolism. In addition to applications in oncology, the most commonly used probe of [1-13C] pyruvate has shown potential in assessing neuroinflammation-linked metabolism in mouse models of multiple sclerosis and traumatic brain injury. Here, we wished to investigate LPS-induced neuroinflammatory changes using HP [1-13C] pyruvate and HP 13C urea.\n\n2D chemical shift imaging following simultaneous intravenous injection of HP [1-13C] pyruvate and HP 13C urea was performed at baseline (day 0), day 3 and day 7 post intracranial injection of LPS (n=6) or saline (n=5). Immunofluorescence (IF) analyses were performed for Iba1 (resting and activated microglia/macrophages), GFAP (resting and reactive astrocytes) and CD68 (activated microglia/macrophages).\n\nA significant increase in HP [1-13C] lactate production was observed in the injected (ipsilateral) side at 3 and 7 days of the LPS-treated mouse brain, but not in either the contralateral side or saline-injected animals. HP 13C lactate/pyruvate ratio, without and with normalization to urea, was also significantly increased in the ipsilateral LPS-injected brain at 7 days compared to baseline. IF analyses showed a significant increase in CD68 and GFAP at 3 days, followed by increased numbers of Iba1 and GFAP positive cells at 7 days post-LPS injection.\n\nIn conclusion, we can detect LPS-induced changes in the mouse brain using HP 13C MRS, in alignment with increased numbers of microglia/macrophages and astrocytes. This study demonstrates that HP 13C spectroscopy holds much potential for providing non-invasive information on neuroinflammation.

immunology↗