Biology subjects

Orset, C.

Publications and source records attributed to Orset, C..

5 recordsLinked to original sources

bioRxiv2024

3D Transcranial ultrasound localization microscopy reveals major arteries in the sheep brain

ObjectiveStroke, a leading cause of mortality and disability globally, demands swift and accurate diagnosis for effective treatment. Although MRI and CT scans serve as conventional methods, their accessibility remains a challenge, prompting exploration into alternative, portable, and non-ionizing imaging solutions like ultrasound with reduced costs. While Ultrasound Localization Microscopy (ULM) displays potential in high-resolution vessel imaging, its 2D constraints limit its emergency utility. Materials and MethodsThis study delves into the feasibility of 3D ULM with multiplexed probe for transcranial vessel imaging in sheep brains, emulating human skull characteristics. Three sheep underwent 3D ULM imaging, compared with angiographic MRI, while skull characterization was conducted in vivo using ultrashort bone MRI sequences and ex vivo via micro CT. Results and conclusionsThe study showcased 3D ULMs ability to highlight vessels, down to the Circle of Willis, yet within a confined 3D field-of-view. Future enhancements in signal, aberration correction, and human trials hold promise for a portable, volumetric, transcranial ultrasound angiography system. Summary statement3D Ultrasound localization microscopy, using a low-frequency matrix probe, enables transcranial reconstruction of the main vessels in sheep brains.

physiology↗

bioRxiv2023

Single nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke

Reactive neuroglia critically shape the brains response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition and microenvironment of the early ischemic lesion. Here we generated a single cell resolution transcriptomics dataset of the injured brain during the acute recovery from permanent middle cerebral artery occlusion. This approach unveiled infarction and subtype specific molecular signatures in oligodendrocyte lineage cells and astrocytes, which ranged among the most transcriptionally perturbed cell types in our dataset. Specifically, we characterized and compared infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and heterogeneous reactive astrocyte populations. Our analyses unveiled unexpected commonalities in the transcriptional response of oligodendrocyte lineage cells and astrocytes to ischemic injury. Moreover, OPCs and reactive astrocytes were involved in a shared immuno-glial cross talk with stroke specific myeloid cells. In situ, osteopontin positive myeloid cells accumulated in close proximity to proliferating OPCs and reactive astrocytes, which expressed the osteopontin receptor CD44, within the perilesional zone specifically. In vitro, osteopontin increased the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition and microenvironment of infarcted brain tissue in the early stages of recovery.

neuroscience↗

bioRxiv2023

Leptomeningeal collaterals regulate reperfusion in ischemic stroke

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet unknown functions. Utilizing a thrombin-based mouse model of stroke and the gold standard fibrinolytic treatment rt-PA, we here show that LMCs play a critical role in preserving vascular function in ischemic territories. We applied laser speckle contrast imaging, ultrafast ultrasound, and two-photon microscopy, to show that after thrombolysis, LMCs allow for gradual reperfusion resulting in small infarcts. On the contrary, in mice with poor LMCs, distal segments of recanalized arteries collapse and deleterious hyperemia causes hemorrhage and mortality. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for gradual reperfusion of ischemic tissues after stroke.

neuroscience↗

bioRxiv2022

The GHB analogue HOCPCA improves sensorimotor function after MCAO via CaMKIIα

Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII) is a major contributor to physiological and pathological glutamate-mediated Ca2+ signals, and its involvement in various critical cellular pathways demands specific pharmacological strategies. We recently presented GHB ligands as the first small molecules selectively targeting the CaMKII hub, a domain primarily responsible for holoenzyme oligomerisation, with an emerging functional role. Here, we report that the GHB ligand, HOCPCA, improves sensorimotor function after experimental stroke in mice when administered at clinically relevant time and in combination with alteplase. We observed that hub modulation by HOCPCA results in differential effects on distinct CaMKII pools, ultimately alleviating aberrant CaMKII signalling after cerebral ischemia. As such, HOCPCA normalised cytosolic Thr286 autophosphorylation after ischemia in mice and downregulated the ischemia-specific expression of a constitutively active CaMKII kinase fragment. Previous studies suggest holoenzyme stabilisation as a potential mechanism, yet a causal link to in vivo findings requires further studies. HOCPCAs selectivity and absence of effects on physiological CaMKII signalling highlight pharmacological modulation of the CaMKII hub domain as an attractive neuroprotective strategy.

pharmacology and toxicology↗

bioRxiv2022

Imaging cerebral arteries tortuosity and velocities by transcranial Doppler ultrasound is a reliable assessment of brain aneurysm in mouse models

Background and PurposeIntracranial aneurysms (IAs) are common vascular abnormalities of the brain with a prevalence of 3.2% in the general population. In the past few decades, several pathophysiological processes leading to IA rupture were identified, including irregular IA shape, an altered hemodynamic stress within the IA and vessel wall inflammation. The use of preclinical models of IA and imaging tools are paramount to better understand the underlying disease mechanisms. Therefore, there is a need for imaging methods to monitor intracranial aneurysm formation. MethodsWe used two established mouse models of IA and we analyzed the progression of the IA by magnetic resonance imaging (MRI), transcranial Doppler (TCD), and histological studies. ResultsIn both models of IA, we observed by TCD a significant decrease of the blood velocities and wall shear stress of the internal carotid arteries (ICA). We also observed the formation of tortuous arteries in both models which were correlated with the presence of an aneurysm as confirmed by MRI and histological analysis. A high grade of tortuosity has been associated with a significant decrease of the mean blood flow velocities and a greater artery dilation. ConclusionsTCD is robust and easy imaging method to evaluate the progression of IA. The decrease of the blood flow velocities and the tortuosity can be used as reliable readout for IA detection.

pathology↗