Biology subjects

Pezet, S.

Publications and source records attributed to Pezet, S..

5 recordsLinked to original sources

bioRxiv2024

Development of a novel, non-invasive and whole brain biomarker of demyelination in a mouse model of multiple sclerosis

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), affecting 2.8 million people worldwide, that presents multiple features, one of which is demyelination. Although treatments exist to manage the condition, no cure has been found to stop the progression of neurodegeneration. To develop new treatments and investigate the multiple systems impacted by MS, new imaging technologies are needed at the preclinical stage. Functional ultrasound imaging (fUS) has recently been demonstrated to robustly measure brain cerebral blood volume (CBV) dynamics as an indirect measure of neural activity. This study aimed at proposing a new biomarker of de- and/or re-myelination in a mouse model of MS induced by cuprizone. We demonstrate first that extended demyelination induces an increased hemodynamic response in the primary sensory cortex both spatially and temporally, which is consistent with fMRI data collected on MS patients. Second, using descriptors of the evoked hemodynamic response, we show that 3 of these descriptors allows the prediction of the level of myelin in the primary sensory cortex (p=5. 10-5) and the thalamus (p=6. 10-6). The development of such a non-invasive biomarker is crucial in the MS field as is provides an extremely useful tool for both disease follow-up and drug development. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSMultiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system. It is the most common cause of neurological disability in young adults, affecting approximately 2.8 million worldwide. While the field of studies in MS has been very active at identifying the neurobiological cellular and molecular mechanisms underlying MS progression, the number of new treatments has been very limited so far, due to several factors, such as the lack of robust and non-invasive biomarkers of myelin loss in longitudinal studies (measurements during the development of the disease). Unfortunately, quantification of myelin loss, (one of the key neurobiological markers of MS progression) is classically performed post-mortem on fixed tissues, preventing longitudinal studies. Longitudinal follow up of an indirect measure of myelin loss is possible, using magnetic resonance imaging. However, the small size of rodent brains poses a challenge for conventional imaging techniques, requiring the use of high field magnet to achieve the necessary sensitivity and resolution. Added value of this studyIn this study, using a sensitive neuroimaging technique, we developed a simple, non-invasive, predictive biomarker able to quantify the individual amount of myelin content consistently and accurately in brain structures in mice. Implications of all the available evidenceThe development of such a biomarker is extremely important for the MS field as it will accelerate the pre-clinical tests for drug efficacy. The benefits provided by our biomarker encompass: 1) Enhanced sensitivity in individually quantifying myelin content, providing a more comprehensive assessment across diverse brain regions 2) Speeding up the process of the discovery, by reducing the number of animals required per group and 3) It will also likely lead to new scientific outcomes, as many more structures will be studied (most teams and drug compagnies only study the demyelination at the level of the corpus callosum). Finally, from a clinical perspective, given the brain alterations observed in this animal model closely mirror those observed in early stages in patients with MS, we anticipate our biomarker, with minimal additional refinements, to be readily applicable in clinical settings.

neuroscience↗

bioRxiv2024

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Spinal muscular atrophy (SMA) is a rare autosomal recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Spinal Motor Neuron 1). SMA is classically characterized by neuromuscular symptoms, including muscular atrophy, weakness of the proximal muscles, especially those of the lower extremities, and hypotonia. Although originally thought of as a purely motor neuron disease, current research has shown that most, if not all, tissues are affected, including the muscle. Until recently, muscle problems in SMA were predominantly considered a consequence of denervation due to the motor neuron death. However, recent work using muscle-specific mouse models of SMN loss, as well as skeletal stem cell specific models have shown that there are tissue specific problems in muscle due to SMN deficiency. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies - Risdiplam and Nusinersen, which can be administered by Type II patients that have symptom onset later in age. One main challenge for Type II SMA patients treated with Risdiplam and Nusinersen is ongoing muscle fatigue, limited mobility, and other skeletal problems, including hip dysplasia and scoliosis. To date, few molecular studies have been conducted on SMA-patient derived tissues after treatment, limiting our understanding how different organ systems react to the therapies, and what additional combination therapies may be beneficial. With this goal in mind, we collected paravertebral muscle from the surgical discard in a cohort of 8 SMA Type II patients undergoing spinal surgery for scoliosis, as well as 7 non-SMA controls with scoliosis and used RNA-sequencing to characterize their molecular profiles. We observed that despite a restoration of the SMN mRNA and protein levels in these patients - at levels at or above the controls - a subset of patients continued to have alterations in mitochondrial metabolism and other markers of cellular stress.

genetics↗

bioRxiv2023

Backscattering Amplitude in Ultrasound Localization Microscopy

In the last decade, Ultrafast Ultrasound Localisation Microscopy has taken non-invasive deep vascular imaging down to the microscopic level. By imaging diluted suspensions of circulating microbubbles in the blood stream at kHz framerate and localising the center of their individual point spread function with a sub-resolution precision, it enabled to break the unvanquished trade-off between depth of imaging and resolution by microscopically mapping the microbubbles flux and velocities deep into tissue. However, ULM also suffers limitations. Many small vessels are not visible in the ULM images due to the noise level in areas dimly explored by the microbubbles. Moreover, as the vast majority of studies are performed using 2D imaging, quantification is limited to in-plane velocity or flux measurements which hinders the accurate velocity determination and quantification. Here we show that the backscattering amplitude of each individual microbubble can also be exploited to produce backscattering images of the vascularization with a higher sensitivity compared to conventional ULM images. By providing valuable information about the relative distance of the microbubble to the 2D imaging plane in the out-of-plane direction, backscattering ULM images introduces a physically relevant 3D rendering perception in the vascular maps. It also retrieves the missing information about the out-of-plane motion of microbubbles and provides a way to improve 3D flow and velocity quantification using 2D ULM. These results pave the way to improved visualization and quantification for 2D and 3D ULM.

bioengineering↗

bioRxiv2022

Specific and non-uniform brain states during cold perception in mice

The quest to decode the complex supraspinal mechanisms that integrate cutaneous thermal information in the central system is still ongoing. The dorsal horn of the spinal cord is the first hub that encodes thermal input which is then transmitted to brain regions via the spinothalamic and thalamo-cortical pathways. So far, our knowledge about the strength of the interplay between the brain regions during thermal processing is limited. To address this question, we imaged the brains of awake and freely-moving mice using Functional Ultrasound imaging during plantar exposure to constant and varying temperatures. Our study, a synchronous large field investigation of mice brains reveals for the first time the brain states and the specific dynamic interplay between key regions involved in thermal processing. Our study reveals: i) a dichotomy in the response of the somato-motor-cingulate cortices and the hypothalamus, which was never described before, due to the lack of appropriate tools to study such regions with both good spatial and temporal resolutions. ii) We infer that cingulate areas may be involved in the affective responses to temperature changes. iii) Colder temperatures (ramped down) reinforces the disconnection between the somato-motor-cingulate and hypothalamus networks. iv) Finally, we also confirm the existence in the mouse brain of a dynamic brain mode characterized by low cognitive strength, described previously only in non-human primates and humans. The present study points towards the existence of a common hub between somato-motor and cingulate regions, whereas hypothalamus functions are related to a secondary network.

neuroscience↗

bioRxiv2021

Volumetric ultrasound localization microscopy of the whole brain microvasculature

Technologies to visualize whole organs across scales in vivo are essential for our understanding of biology in health and disease. To date, only post-mortem techniques such as perfused computed tomography scanning or optical microscopy of cleared tissues achieve cellular resolution across entire organs and imaging methods with equal performance in living mammalian organs have yet to be developed. Recently, 2D ultrasound localization microscopy has successfully mapped the fine-scale vasculature of various organs down to a 10 m precision. However, reprojection issues and out-of-plane motion prevent complex blood flow quantification and fast volumetric imaging of whole organs. Here, we demonstrate for the first time in vivo volumetric ultrasound localization microscopy mapping of the rodent brain vasculature. We developed a complete methodological pipeline that includes specific surgery, a dedicated 3D ultrasound acquisition sequence, localization and tracking algorithms, motion correction and realignment, as well as the post-processing quantification of cerebral blood flow. We illustrate the power of this approach, by mapping the whole rat brain vasculature at a resolution of 12 m, revealing mesoscopic to macroscopic vascular architectures and cerebral blood flows ranging from 1 to 100 mm/s. Our results pave the way to the investigation of in vivo vascular processes across the mammalian brain in health and disease, in a wide range of contexts and models.

bioengineering↗