Biology subjects

Le Gac, B.

Publications and source records attributed to Le Gac, B..

6 recordsLinked to original sources

bioRxiv2026

Associations Between the IL-23/IL-17A Cytokine Axis and Ambulatory Blood Pressure in Older Adults

BackgroundHypertension, the persistent elevation of blood pressure (BP), is characterized by chronic low-grade inflammation and systemic cytokine release. Circulating cytokines contribute to the development of hypertension and end-organ damage. However, the specific immune profile associated with the progression of hypertension remains unclear. We hypothesize that a plasma cytokine signature reflects early BP changes in older adults. MethodsSeventy participants aged 57-81 years were categorized as normotensive (n = 17), elevated BP (n = 10), or hypertensive (n = 43) based on 24-hour ambulatory BP monitoring and antihypertensive treatment status. Plasma IL-1{beta}, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, and TNF- were quantified using immunoassays. Partial Pearson correlations adjusted for demographic and biochemical covariates were used to assess associations between cytokines, BP, and cytokine-cytokine networks. ResultsIn untreated hypertensive individuals, plasma IL-23 was positively correlated with 24-hour diastolic BP. Antihypertensive treatment was associated with reduced IL-17A concentrations, which are negatively associated with 24-hour systolic BP. In the elevated BP group, IL-21 concentrations were higher than in normotensive individuals. To further characterize the cytokine signature, cytokine-cytokine correlations were examined. IL-23 and IL-17A were positively correlated with most interleukins, whereas TNF- showed few associations. IL-1{beta} exhibited strong correlations with both IL-23 and IL-17A, particularly in untreated participants. ConclusionIL-23 and IL-17A are associated with BP status and are broadly interconnected with other inflammatory cytokines, highlighting the potential importance of the IL-23/IL-17A axis in the hypertension of development. Early alterations in IL-21 in elevated BP may reflect immune changes that precede the onset of hypertension.

physiology↗

bioRxiv2024

Bidirectional control of neurovascular coupling by cortical somatostatin interneurons

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is altered early in neurological disorders and underlies functional brain imaging. This process involves numerous cellular players. Among them inhibitory interneurons receive increasing attention, but how they control blood flow remains elusive. This study elucidates the mechanisms by which somatostatin interneurons bidirectionally control neurovascular coupling. Patch clamp recordings in, ex vivo, cortical slices from mice expressing channelrhodopsin-2 in somatostatin interneurons, revealed that these neurons are supralinearly activated at low-frequencies (< 5 Hz) and efficiently photostimulated at frequencies up to 20 Hz. Ex vivo vascular imaging showed that low-frequency (2 Hz) photostimulation triggered vasodilation whereas high-frequency (20 Hz) photostimulation induced vasoconstriction. Histochemistry revealed that subpopulations of cortical somatostatin interneurons expressed the neuronal nitric oxide synthase, and/or neuropeptide Y to a greater extent. Consistently, pharmacological investigations showed that vasodilation induced by low-frequency photostimulation involves nitric oxide release and activation of soluble guanylate cyclase. In contrast, the vasoconstriction induced at high-frequency photostimulation involves neuropeptide Y release and activation of the Y1 vascular receptor. These findings provide valuable insights into neurovascular coupling and help to understand the cellular mechanism underlying the functional brain imaging signals.

neuroscience↗

bioRxiv2024

Elevated pyramidal cell firing orchestrates arteriolar vasoconstriction through COX-2-derived prostaglandin E2 signaling

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is essential for brain function and underpins functional brain imaging. Whereas mechanisms involved in vasodilation are well-documented, those controlling vasoconstriction remain overlooked. This study unravels the mechanisms by which pyramidal cells elicit arteriole vasoconstriction. Using patch-clamp recording, vascular and Ca2+ imaging in mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces vasoconstriction, correlating with firing frequency and somatic Ca2+ increase. Ex vivo and in vivo pharmacological investigations indicate that this vasoconstriction predominantly recruits prostaglandin E2 through the cyclooxygenase-2 pathway, and activation of EP1 and EP3 receptors. We also present evidence that specific interneurons releasing neuropeptide Y, and astrocytes, through 20-hydroxyeicosatetraenoic acid, contribute to this process. By revealing the mechanisms by which pyramidal cells lead to vasoconstriction, our findings shed light on the complex regulation of neurovascular coupling. Significance statementCerebral blood flow is tightly controlled by neuronal activity, a process termed neurovascular coupling which serves as the physiological basis for functional brain imaging widely used to map neuronal activity in health and diseases. While the prevailing view links increased neuronal activity with enhanced blood perfusion, our data suggest that elevated neuronal activity can also reduce cerebral blood flow. By optically controlling the activity of pyramidal cells, we demonstrate that these excitatory neurons induce vasoconstriction when their action potential firing is increased by releasing glutamate and lipid messengers. These findings update the interpretation of functional brain imaging signals and help to better understand the etiopathogenesis of epilepsy and Alzheimers disease, in which hyperactivity, hypoperfusion and cognitive deficits overlap.

neuroscience↗

bioRxiv2023

Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis

Brain water homeostasis not only provides a physical protection, but also determines the diffusion of chemical molecules key for information processing and metabolic stability. As a major type of glia in brain parenchyma, astrocytes are the dominant cell type expressing aquaporin water channel. How astrocyte aquaporin contributes to brain water homeostasis in basal physiology remains to be understood. We report that astrocyte aquaporin 4 (AQP4) mediates a tonic water efflux in basal conditions. Acute inhibition of astrocyte AQP4 leads to intracellular water accumulation as optically resolved by fluorescence-translated imaging in acute brain slices, and in vivo by fiber photometry in mobile mice. We then show that aquaporin-mediated constant water efflux maintains astrocyte volume and osmotic equilibrium, astrocyte and neuron Ca2+ signaling, and extracellular space remodeling during optogenetically induced cortical spreading depression. Using diffusion-weighted magnetic resonance imaging (DW-MRI), we observed that in vivo inhibition of AQP4 water efflux heterogeneously disturbs brain water homeostasis in a region-dependent manner. Our data suggest that astrocyte aquaporin, though bidirectional in nature, mediates a tonic water outflow to sustain cellular and environmental equilibrium in brain parenchyma. Significance statementOur brain is immersed, thus protected, in a water environment. It ensures intra- and extracellular molecular diffusion, which is vital for brain function and health. Brain water homeostasis is maintained by dynamic water transport between different cell types. Astrocytes are a main type of glial cell widely distributed in brain parenchyma, expressing the bidirectional aquaporin water channel. Here we show that in basal conditions, aquaporin channel mediates a tonic water efflux from astrocytes. This mechanism maintains astrocyte volume stability, activity-gated brain parenchyma remodeling and brain water homeostasis. Our finding sheds light on how astrocytes regulate water states in the brain, and will help to understand brain allostasis in specific life contexts.

physiology↗

bioRxiv2022

Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain

Cav3.2 T-type calcium channel is a major molecular actor of neuropathic pain in peripheral sensory neurons, but its involvement at the supra-spinal level is almost unknown. In the Anterior Pretectum (APT), a hub of connectivity of the somatosensory system involved in pain perception, we show that Cav3.2 channels are expressed in a sub-population of GABAergic neurons co-expressing parvalbumin (PV). In these PV-expressing neurons, Cav3.2 channels contribute to a high frequency bursting activity, which is increased in the spared nerve injury model of neuropathy. Specific deletion of Cav3.2 channels in APT neurons reduced both the initiation and maintenance of mechanical and cold allodynia. These data are a direct demonstration that centrally expressed Cav3.2 channels also play a fundamental role in pain pathophysiology.

neuroscience↗

bioRxiv2021

LACTATE IS A MAJOR ENERGY SUBSTRATE FOR CORTICAL NEURONS AND ENHANCES THEIR FIRING ACTIVITY

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with Kir6.2 and SUR1 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function. HighlightsO_LIMost cortical neurons subtypes express pancreatic beta-cell like KATP channels. C_LIO_LILactate enhances spiking activity via its uptake and closure of KATP channels. C_LIO_LICortical neurons take up and oxidize lactate. C_LIO_LICortical neurons produce ATP mainly by oxidative phosphorylation. C_LI

neuroscience↗