Wise, B. | Search bioRxiv

bioRxiv2026

3D Light Sheet Microscopy Reveals Aging Osteoarthritis-associated Joint-innervated Nerve Remodeling in Mouse Knee Joints

ObjectivesOsteoarthritis (OA) is a prevalent age related joint disease-causing chronic pain. This study investigated how nociceptive and sympathetic nerve innervation in the mouse knee joint changes with age and OA progression, and how these changes relate to pain and disease severity. MethodsThirty-eight mice were assigned to four groups: young male (My), aged male (Ma), young female (Fy), and aged female (Fa). Pain sensitivity was evaluated via Pressure Application Measurement (PAM), and joint damage was graded using OARSI scoring. CGRP and PIEZO2 expressions in dorsal root ganglia (DRG) were also assessed. We employed iDISCO tissue clearing and 3D light sheet fluorescence microscopy to visualize total (PGP9.5), nociceptive (CGRP), and sympathetic (TH) nerve fibers in anterior regions of mouse knee joints. A MATLAB-based tool quantified nerve architecture. ResultsThe Ma group displayed the highest OA severity and markedly lower mechanical withdrawal thresholds compared with My (H = 11.59, {varepsilon}{superscript 2} = 0.64), suggesting an age effect on pain-related behavior. This phenotype was accompanied by a higher total PGP9.5 nerve fiber density in the knee joint (mean difference -0.3127, 95% CI -0.4551 to -0.1704) and increased CGRP nociceptive innervation. In contrast, female mice showed no age-dependent change in PAM withdrawal thresholds, consistent with preserved cartilage integrity and stable OARSI scores, and no detectable age-related differences in PGP9.5 or CGRP innervation. The TH sympathetic fiber distribution was comparable across sexes and ages. Consistent with joint-level findings, DRG analyses demonstrated increased CGRP and PIEZO2 expression in the Ma group, whereas females exhibited no significant change. ConclusionEnhanced nociceptive but not sympathetic nerve remodeling in knee cavities is associated with increased OA severity and knee pain in the Ma group. These findings emphasize the role of peripheral sensory plasticity in OA pain and demonstrate the value of 3D imaging for visualizing neuroanatomical changes in joint disorders.

neuroscience↗

bioRxiv2024

Ungulate personality and the human shield contribute to long-distance migration loss

Long-distance ungulate migrations are declining and past research has focused on preserving migration paths where habitat fragmentation and loss disrupts movement corridors. However, changing residency-migration tradeoffs are the stronger driver of long-distance migration loss in some populations. The human shield effect relative to predation risk and anthropogenic food resources likely shapes these tradeoffs, but individual animals also vary in their propensity to tolerate proximity to humans and developed areas. We investigated how personality relative to human-habituation affects migration behavior. We categorized elk as bold or shy based on use of anthropogenic food resources identified through a clustering algorithm applied to GPS collar data. Bold elk were 4 times more likely to select wintering areas close to human activity and migrated 60% shorter distances compared to shy elk. As a result, elk wintering grounds were spatially structured such that conflict- and disease-prone individuals selected areas adjacent to human activity. Our results suggest that bold personality traits act as a precursor to human-habituation, which permits bold elk to reap the forage and predation rewards that occur in suburban landscapes. A multi-pronged approach beyond just maintaining habitat corridors may be necessary to conserve long-distance migrations for species that can become human-habituated.

ecology↗