Khondker, A. | Search bioRxiv

bioRxiv2024

Treadmill step training promotes corticospinal tract plasticity after incomplete spinal cord injury

Spinal cord injury (SCI) often impairs motor functions such as voluntary movement and fine motor control, with the corticospinal tract (CST) being a crucial pathway affected. While CST-targeted rehabilitation, such as treadmill training, supports motor recovery, gaps remain in understanding the topographical changes within the CST and how they correlate with behavioral outcomes. In this study, we utilized a custom Emx1Cre;LSL-SynGFP mouse line to quantify CST plasticity following moderate contusion SCI, both with and without exercise (treadmill) training. Fluorescent labeling of cortical synapses allowed for detailed visualization of descending CST rewiring, and we assessed its relationship to behavioral outcomes, including kinematics analysis and motivational state. Mice were stratified by motivational state using the Progressive Ratio Assay, and locomotor recovery was evaluated through the Basso Mouse Scale (BMS), joint/limb kinematics, and Motion Sequencing (MoSeq) analysis. Our findings indicate that treadmill training enhances CST rewiring, especially in highly motivated animals, leading to increased synaptic density in the ventral horn and improved BMS subscores. Motivation further influenced specific kinematic parameters, such as toe clearance, while treadmill training significantly improved speed by reducing the stance phase. Results suggest that while treadmill training induces broad beneficial outcomes, motivation may fine-tune recovery, influencing neural circuit and behavioral changes. This suggests multiple mechanisms converge to promote recovery--those we cannot control and those we can. These results underscore the combined role of task-specific training and also perhaps motivation in driving CST plasticity and functional recovery after SCI.

neuroscience↗

bioRxiv2020

Order and disorder - an integrative structure of the full-length human growth hormone receptor

Despite the many physiological and pathophysiological functions of the human growth hormone receptor (hGHR), a detailed understanding of its modus operandi is hindered by the lack of structural information of the entire receptor at the molecular level. Due to its relatively small size (70 kDa) and large content of structural disorder (>50%), this membrane protein falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small angle-X-ray scattering (SAXS) as the foundation. We developed an approach in which we combined SAXS, X-ray diffraction and NMR spectroscopy obtained on the individual domains and integrated the data through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs. The structure of the hGHR was determined in its monomeric state and provides the first experimental model of any full-length cytokine receptor in a lipid membrane. Combined, our results highlight that the three domains of the hGHR are free to reorient relative to each other, resulting in a broad structural ensemble. Our work exemplifies how integrating experimental data from several techniques computationally, may enable the characterization of otherwise inaccessible structures of membrane proteins with long disordered regions, a widespread phenomenon in biology. To understand orchestration of cellular signaling by disordered chains, the hGHR is archetypal and its structure emphasizes that we need to take a much broader, ensemble view on signaling.

biophysics↗