Biology subjects

Meisel, A.

Publications and source records attributed to Meisel, A..

5 recordsLinked to original sources

bioRxiv2026

ABERRANT HIPPOCAMPAL NEUROGENESIS IS A CONSERVED RESPONSE TO STROKE IN MICE: A MULTI-CENTER MULTIMODEL STUDY

BackgroundAdult hippocampal neurogenesis is markedly altered after cerebral ischemia. Although stroke increases the production of newborn neurons, many of these cells display aberrant morphological and positional features that impair their functional integration and contribute to long-term cognitive decline. Given the clinical heterogeneity of ischemic stroke and the persistent translational failures of preclinical approaches relying on single-model studies it remains unknown whether post-stroke neurogenic alterations are conserved across different experimental paradigms. This study aimed to define common and model-specific features of hippocampal neurogenesis across complementary focal ischemia models. MethodsWe performed a multi-center, multimodel analysis within the STROKE-IMPaCT consortium using permanent and transient middle cerebral artery occlusion (MCAO) paradigms (MCAO via ligation or cauterization under normoxic (dMCAO) or hypoxic conditions (dMCAO+Hypoxia); and filament-based tMCAO across six international sites. Brains from adult C57BL/6J mice were collected 3 days, 7 days, or 2 months after ischemia, sham, or naive conditions. Hippocampal cell proliferation (Ki67) and neuroblast density (DCX) were quantified, and the morphological maturation of newborn neurons was evaluated using high-resolution analyses of dendritic architecture and somatodendritic polarity. All analyses were performed blind to experimental group. ResultsAcross all stroke models, ischemia induced a robust bilateral increase in hippocampal cell proliferation, most pronounced at 3 days and still elevated at 7 days, with levels returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized by 2 months. Despite recovery in cell number, long-term morphological analysis revealed a consistent reduction in apical dendrite length and a higher proportion of neurons exhibiting aberrant features including ectopic localization, multipolar or inverted polarity, and abnormal lateral growth across all models. These abnormalities were observed both when pooling data across sites and when analyzing each model or center individually. ConclusionsIschemia induces an early, transient increase in hippocampal neurogenesis across diverse stroke paradigms, but the newborn neurons generated after stroke consistently display maladaptive morphological features. These cross-model, cross-site abnormalities indicate that aberrant hippocampal neurogenesis represents a robust hallmark of post-stroke pathology within the investigated species, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across experimental stroke models. Our findings support the concept that maladaptive neurogenesis may contribute to chronic post-stroke cognitive impairment and underscore the need to consider the quality not only the quantity of newborn neurons when developing therapeutic strategies.

animal behavior and cognition↗

bioRxiv2025

Assessing post-stroke cognition in pre-clinical models: lessons and recommendations from a multi-center study

Cognitive decline is a significant long-term consequence of stroke and has no available treatments. To aid in therapy development, we sought to achieve robust detection of cognitive performance after stroke in a multi-site design. Ischemic stroke was induced in adult and middle-aged male C57BL/6J mice utilizing three well-established models: distal middle cerebral artery occlusion (dMCAO), dMCAO with hypoxia and transient MCAO. Cognitive outcomes were assessed via Novel Object Recognition (NOR) and Barnes Maze (BM) tests prior to surgery, and during sub-acute (1-2 weeks) and chronic (8 weeks) phases post-stroke. Histology and immunostaining were used to assess infarct size, tissue damage and neuronal loss, and plasma neurofilament light was quantified. We did not detect a reliable cognitive deficit after stroke using NOR but saw a promising signal from BM (single site tested only). Overall, our study highlights the often-encountered challenges in detecting post-stroke cognitive impairment within the pre-clinical stroke community, as well as a number of complexities in the design and execution of pre-clinical stroke cognition studies, particularly as applied to a multi-site structure. We provide recommendations and suggest important aspects of stroke cognition studies to consider in the future, whether operating as an individual lab or a multi-site group.

animal behavior and cognition↗

bioRxiv2024

Ide copy number variant does not influence lesion size and mortality in two C57BL/6J mouse models of cerebrovascular ischemia nor in human cerebrovascular disease. An exploratory study

Contrary to the common belief, the most commonly used laboratory mouse inbred strains are shaped by a distinctive genetic and phenotypic diversity. In the past 10 years next generation sequencing unveiled a wide spectrum of genetic variants in different mouse inbred strains and the meticulous observation of researchers pointed to a variegate intra-and inter-strain phenotypic diversity. Although a genotype-phenotype correlation has been described for some traits, the relationship between several endophenotypes and causative genetic variability remains still unknown. Recently, we characterized the brain collateral plasticity in two brain ischemia C57BL/6J mouse models (i.e bilateral common carotid artery stenosis [BCCAS] and 60-min transient unilateral middle cerebral artery occlusion [MCAO]) and observed a Mendelian-like fashion of inheritance of the posterior communicating artery (PcomA) plasticity. Interestingly, a copy number variant (CNV) spanning Ide locus was reported to segregate in an analogous Mendelian-like pattern in the C57BL/6J colonies of the Jackson Laboratory. Given the critical role of Ide in vascular plasticity, Ide CNV was an excellent candidate to explain PcomA variability in C57BL/6J inbred mice. To investigate this hypothesis, we applied a combination of complementary techniques (i.e T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) to characterize the collaterome in C57BL/6J BCCAS and MCAO mice and performed on these Taqman genotyping, exome sequencing, and RNA sequencing. We report an Ide CNV in a BCCAS mouse with 2 patent PcomAs. We then investigated the hypothesis that IDE gain and loss of function mutations may have influenced the vascular phenotype in a cohort of 438,250 cases and controls (UK Biobank) and 15,790 neurological patients (Genomics England), respectively. We identified four IDE CNVs resulting in a loss of function (LoF) in one patient with hereditary ataxia, a patient with hereditary congenital heart disease and two healthy individuals. In addition, we report four IDE LoF point mutations (p.Leu5X, p.Met394ValfsX29, p.Pro14SerfsX26, p.Leu889X) present in controls or inherited from healthy parents. Ide CNV and LoF variants do not crucially influence PcomA variability in C57BL/6J inbred mice and do not cause a vascular phenotype in humans.

genetics↗

bioRxiv2021

Rest/Stress Myocardial Perfusion Imaging by Positron Emission Tomography with 18F-Flurpiridaz: A Feasibility Study in Mice

BackgroundMyocardial perfusion imaging by positron emission tomography (PET-MPI) is the current gold standard for quantification of myocardial blood flow. 18F-flurpiridaz was recently introduced as a valid alternative to currently used PET-MPI probes. Nonetheless, optimum scan duration and time interval for image analysis are currently unknown. Further, it is unclear whether rest/stress PET-MPI with 18F-flurpiridaz is feasible in mice. MethodsRest/stress PET-MPI was performed with 18F-flurpiridaz (0.6-3.0 MBq) in 29 mice aged 7-8 months. Regadenoson (0.1 g/g) was used for induction of vasodilator stress. Kinetic modeling was performed using a metabolite-corrected arterial input function. Image-derived myocardial 18F-flurpiridaz uptake was assessed for different time intervals by placing a volume of interest in the left ventricular myocardium. ResultsTracer kinetics were best described by a two-tissue compartment model. K1 ranged from 6.7-20.0 mL/cm3/min, while myocardial volumes of distribution (VT) were between 34.6 and 83.6 mL/cm3. Of note, myocardial 18F-flurpiridaz uptake (%ID/g) was significantly correlated with K1 at rest and following pharmacological stress testing for all time intervals assessed. However, while Spearmans coefficients (rs) ranged between 0.478 and 0.672, R2 values were generally low. In contrast, an excellent correlation of myocardial 18F-flurpiridaz uptake with VT was obtained, particularly when employing the averaged myocardial uptake from 20-40 min post tracer injection (R2 [≥]0.98). Notably, K1 and VT were similarly sensitive to pharmacological stress induction. Further, mean stress-to-rest ratios of K1, VT, and %ID/g 18F-flurpiridaz were virtually identical, suggesting that %ID/g 18F-flurpiridaz can be used to estimate CFR in mice. ConclusionOur findings suggest that a simplified assessment of relative myocardial perfusion and coronary flow reserve (CFR), based on image-derived tracer uptake, is feasible with 18F-flurpiridaz in mice, enabling high-throughput mechanistic CFR studies in rodents.

physiology↗

bioRxiv2020

Glycolic acid protects neurons against ischemia in vitro and in two animal models of stroke

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, re-open occluded arteries but do not protect against ischemia-induced damage that has already occurred before reperfusion or ischemia/reperfusion-induced neuronal damage. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in C. elegans, dauer larva, while GA itself can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study, we tested the protective effect of GA in different ischemia models, including commonly used stroke models in mice and swine. Our results show that GA, given during reperfusion, strongly protects against ischemic damage and improves the functional outcome. We provide evidence that GA exerts its effect by counteracting the glutamate-dependent increase in intracellular calcium during excitotoxicity. These results suggest that GA treatment has the potential to reduce the mortality and disability caused by stroke in patients.

neuroscience↗