Wiedermann, D. | Search bioRxiv

bioRxiv2025

Dynamic structural connectivity changes in cortical and cortico-striatal strokes in mice

Stroke is a primary global health concern, leading to significant mortality and long-term disability. Beyond immediate neuronal damage, functional and structural connectivity is altered brain-wide with implications for functional deficits and recovery. It remains unclear, however, if the level of degeneration, i.e. reduced myelination and axonal damage, as well as compensatory plasticity, i.e., axonal sprouting and remyelination, depend on the lesion size and topology. This study compares for the first time two different stroke models in adult male mice, with the aim of uncovering the dynamics in white matter changes. Repetitive diffusion magnetic resonance imaging (dMRI) over four weeks post photothrombotic cortical (1.41{+/-}0.92% of brain volume), and middle cerebral artery occlusion (MCAO) cortico-striatal (11.53{+/-}2.8% of brain volume), strokes were used to map structural connectivity changes at the whole-brain level. We quantified inter- and intra-hemispheric seed strength changes over time, with seed strength reflecting how strongly each region is connected to the rest of the brain. Differences between groups and time points were assessed using a mixed model corrected for multiple comparisons. In conclusion, large cortico-striatal lesions led to increased structural connectivity in sensorimotor regions, whereas small cortical lesions induced asymmetric connectivity changes: an increase extending globally from the ischemic hemisphere and a decrease expanding globally from the healthy hemisphere. These findings highlight that stroke severity and lesion size significantly affect the temporal dynamics and spatial distribution of connectivity disruptions, emphasizing the need for targeted monitoring of neural changes post-stroke. Significance statementPathophysiological changes close to an ischemic lesion are well understood. But structurally connected regions also undergo stroke-related changes potentially contributing to functional deficits. Animal studies using in vivo diffusion MRI to quantify white matter changes have been limited to single connections, time points after stroke, and basic diffusion measures. We provide the first in-depth characterization of whole-brain fiber tracking to compare small cortical and large cortico-striatal strokes. We found a complex dynamic of decreasing and increasing structural connectivity in single sensorimotor-related brain regions within the brain network - even remote areas from the stroke lesion. This study provides a better understanding of the interactions of regions during stroke recovery, which may help in developing therapies targeting localized white matter repair.

neuroscience↗

bioRxiv2022

Selectively expressed RNA molecules: a new dimension infunctionalized cell targeting

Exact targeting of specific mammalian cell types or diseased cells is one of the most urgently needed prerequisites for a new generation of potent pharmaceuticals. Different approaches have been pursued, failing mainly due to a lack of specific surface markers in most cases. Developing a completely novel RNA-based methodology, we can now ensure exact cell targeting and simultaneously combine this with selective expression of effector proteins, thereby functionalization of the target cell for therapy, diagnostics or cell steering. The specific combination of the molecular properties of antisense technology and mRNA therapy with functional RNA secondary structures allowed us to develop selectively expressed RNA molecules for medical applications. These so-called seRNAs remain inactive in non-target cells and are only activated by partial degradation to induce translation in preselected cell types of interest. Cell type specificity and type of functionalization are easily adaptable based on a simple modular system. In proof of concept in vitro and in vivo studies we used seRNAs as a highly selective platform technology for powerful glioblastoma cancer cell targeting and significantly reduce brain tumors of mice without detectable side effects with just a single treatment within days. Our data open up new potential avenues for the efficient treatment of various cancers and other human diseases.

cell biology↗