Biology subjects

Weidner, N.

Publications and source records attributed to Weidner, N..

4 recordsLinked to original sources

bioRxiv2024

Biomaterial Scaffold Stiffness Influences the Foreign Body Reaction, Tissue Stiffness, Angiogenesis and Neuroregeneration in Spinal Cord Injury

Biomaterial scaffold engineering presents great potential in promoting axonal regrowth after spinal cord injury (SCI), yet persistent challenges remain, including the surrounding host foreign body reaction and improper host-implant integration. Recent advances in mechanobiology spark interest in optimizing the mechanical properties of biomaterial scaffolds to alleviate the foreign body reaction and facilitate seamless integration. The impact of scaffold stiffness on injured spinal cords has not been thoroughly investigated. Herein, we introduce stiffness-varied alginate anisotropic capillary hydrogel scaffolds implanted into adult rat C5 spinal cords post-lateral hemisection. Four weeks post-implantation, scaffolds with a stiffness approaching that of the spinal cord effectively minimize the host foreign body reaction via yes-associated protein (YAP) nuclear translocation. Concurrently, the softest scaffolds maximize cell infiltration and angiogenesis, fostering significant axonal regrowth but limiting the rostral-caudal linear growth. Furthermore, as measured by atomic force microscopy (AFM), the surrounding spinal cord softens when in contact with the stiffest scaffold while maintaining a natural level in contact with the softest one. In conclusion, our findings underscore the pivotal role of stiffness in scaffold engineering for SCI in vivo, paving the way for the optimal development of efficacious biomaterial scaffolds for tissue engineering in the central nervous system.

neuroscience↗

bioRxiv2022

PRE-INJURY MECHANORECEPTOR ABLATION REDUCES NOCICEPTOR-DRIVEN SPINAL CORD INJURY-INDUCED NEUROPATHIC PAIN

Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptors before SCI mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations of contusion SCI mice 7 days after injury makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

neuroscience↗

bioRxiv2022

Intermediate Gray Matter Interneurons in the Lumbar Spinal Cord Play a Critical and Necessary Role in Coordinated Locomotion

Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of unique spinal interneuron (SpIN) subtypes, the phenotype of combined premotor interneuron loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two-weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system which strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VII in spinal L2-L4 correlates with hindlimb dysfunction. White matter damage and lower motoneuron loss did not correlate with behavioral deficits. Animals do not regain lost sensorimotor function three months after injury, indicating that natural recovery of the spinal cord cannot compensate for loss of laminae V-VII neurons. As spinal cord injuries are often located at spinal enlargements, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function. HighlightsO_LIFunctional deficits in coordination, balance, rhythmic walking and gait follow two weeks after a lumbar (L2-L4) intermediate (V-VII) gray matter spinal cord injury in rats C_LIO_LIDeficits correlate with neuronal loss in laminae V-VII in spinal levels L2-L4 but do not correlate with lower motoneuron loss or white matter damage nor do animals show signs of sensory dysfunction due to spinal cord injury C_LIO_LICoordination deficits remain after three months, indicating that natural recovery cannot compensate for this interneuronal loss C_LIO_LINewly developed machine-learning models non-invasively fully classify injured animals by functional readouts equivalent to time-intensive endpoint histological analysis C_LI

neuroscience↗

bioRxiv2019

Brain tissue properties and morphometry assessment after chronic complete spinal cord injury

There is much controversy about the potential impact of spinal cord injury (SCI) on brains anatomy and function, which is mirrored in the substantial divergence of findings between animal models and human imaging studies. Given recent advances in quantitative magnetic resonance imaging (MRI) we sought to tackle the unresolved question about the link between the presumed injury associated volume differences and underlying brain tissue property changes in a cohort of chronic complete SCI patients. Using the established computational anatomy methods of voxel-based morphometry (VBM) and voxel-based quantification (VBQ) we performed statistical analyses of grey matter volume and parameter maps indicative for brains myelin, iron and free tissue water content in complete SCI patients (n=14) and healthy individuals (n=14). Our whole-brain analysis showed significant white matter volume loss in the rostral and dorsal part of the spinal cord consistent with Wallerian degeneration of proprioceptive axons in the lemniscal tract in SCI subjects, which correlated with spinal cord atrophy assessed with quantification of the spinal cord cross-sectional area at cervical level. The latter finding suggests that Wallerian degeneration of the lemniscal tract represents a main contributor to the observed spinal cord atrophy, which is highly consistent with preclinical ultrastructural/histological evidence of remote changes in the central nervous system secondary to SCI. Structural changes in the brain representing remote changes in the course of chronic SCI could not be confirmed with conventional VBM or VBQ statistical analysis. Whether and how MRI based brain morphometry and brain tissue property analysis will inform clinical decision making and clinical trial outcomes in spinal cord medicine remains to be determined.

neuroscience↗