Biology subjects

Leergaard, T. B.

Publications and source records attributed to Leergaard, T. B..

3 recordsLinked to original sources

bioRxiv2022

Factor VII activating protease (FSAP) inhibits the outcome of ischemic stroke in mouse models.

Factor VII activating protease (FSAP) is a circulating serine protease, and individuals with the Marburg I (MI) single nucleotide polymorphism (SNP), which results in an inactive enzyme, have an increased risk of stroke. The outcome of ischemic stroke is more marked in FSAP-deficient mice compared to their wild-type (WT) counterparts. Plasma FSAP levels are raised in patients as well as mice after stroke. In vitro, FSAP promotes fibrinolysis by cleavage of fibrinogen, activates protease-activated receptors and decreases the cellular cytotoxicity of histones. Since these are desirable properties in stroke treatment, we tested the effect of recombinant serine protease domain of FSAP (FSAP-SPD) on ischemic stroke in mice. A combination of tissue plasminogen activator (tPA) and FSAP-SPD enhanced clot lysis, improved microvascular perfusion and neurological outcome and reduced infarct volumes in a mouse model of thromboembolic stroke. In the tail bleeding model FSAP-SPD treatment provoked a faster clotting time indicating that it has a pro-coagulant effect that is described before. FSAP-SPD improved stroke outcome and diminished the negative effects of co-treatment with tPA in the transient middle cerebral artery occlusion model. The inactive MI-isoform of FSAP did not have any effects in either model. In mice with FSAP deficiency there were minor differences in the outcomes of stroke but the treatment with FSAP-SPD was equally effective. Thus, FSAP represents a promising novel therapeutic strategy in the treatment of ischemic stroke that requires further evaluation.

biochemistry↗

bioRxiv2021

Topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1

Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. Combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines, and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibres passing the pontine nuclei. We conclude that cortical gradients of area patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei. Summary statementCortical gradient expression of the area patterning gene Nr2f1 spatially and temporally controls corticopontine topographic connectivity in layer V projection neurons.

neuroscience↗

bioRxiv2020

Experimental and computational study on motor control and recovery after stroke: towards a constructive loop betweenexperimental and virtual embodiedneuroscience

Being able to replicate real experiments with computational simulations is a unique opportunity to refine and validate models with experimental data and redesign the experiments based on simulations. However, since it is technically demanding to model all components of an experiment, traditional approaches to modeling reduce the experimental setups as much as possible. In this study, our goal is to replicate all the relevant features of an experiment on motor control and motor rehabilitation after stroke. To this aim, we propose an approach that allows continuous integration of new experimental data into a computational modeling framework. First, results show that we could reproduce experimental object displacement with high accuracy via the simulated embodiment in the virtual world by feeding a spinal cord model with experimental registration of the cortical activity. Second, by using computational models of multiple granularities, our preliminary results show the possibility of simulating several features of the brain after stroke, from the local alteration in neuronal activity to long-range connectivity remodeling. Finally, strategies are proposed to merge the two pipelines. We further suggest that additional models could be integrated into the framework thanks to the versatility of the proposed approach, thus allowing many researchers to achieve continuously improved experimental design.

neuroscience↗