Biology subjects

Cafferty, W. B.

Publications and source records attributed to Cafferty, W. B..

4 recordsLinked to original sources

bioRxiv2026

Spared corticospinal neurons activate an endogenous plasticity program after partial CNS injury

Functional recovery after incomplete spinal cord injury depends substantially on the capacity of anatomically spared neurons to remodel their connections, yet the molecular programs underlying this endogenous plasticity remain poorly understood. To identify and validate these mechanisms, we combined retrograde labeling, unilateral corticospinal tract injury, spatial transcriptomics, and human stem cell-derived neurons. Injured corticospinal neurons exhibited widespread downregulation with remaining activated pathways dominated by stress, cell death, and degenerative programs. In contrast, spared corticospinal neurons activated a coordinated pro-plasticity program characterized by metabolic, immune, and cytoskeletal remodeling together with selective suppression of growth-inhibitory signaling. Network and drug perturbation analyses identified ARHGEF12 suppression and vorinostat treatment as complementary target- and state-based strategies to enhance neurite regeneration in human neurons. Together, these findings define key components of endogenous plasticity and provide a framework for discovering therapeutic targets for neural repair.

neuroscience↗

bioRxiv2025

REVS: A New Open-Source Platform for High-Resolution Analysis of Rodent Wheel Running Behavior

BackgroundRodent wheel running is widely used in neuroscience and preclinical research to assess locomotor function, recovery post-trauma or disease, circadian rhythms, and exercise physiology. However, most existing wheel-running systems offer limited metrics, lack flexibility in hardware, or require costly proprietary software, reducing their usefulness for detailed behavioral phenotyping--especially in models of injury or rehabilitation. New methodWe developed REVS (Revolution Evaluation and Visualization Software), a low-cost, open-source hardware and software platform for analyzing and visualizing rodent wheel running behavior. REVS captures wheel revolutions using Hall effect sensors and computes 13 day-level behavioral metrics along with detailed bout-level data. Users can interactively explore high-resolution temporal features and export data in Open Data Commons (ODC)-compatible formats. REVS supports customizable wheel types, facilitating use in animals with motor and/or sensory impairments. ResultsWe validated REVS using a mouse model of partial spinal cord injury, where fine motor control is compromised. REVS detected impairments in 10 of 13 behavioral metrics post-injury, with varied recovery trajectories across measures. Principal component analysis revealed that recovery was closely linked to bout quality and intensity, rather than timing. Comparison with existing methodsUnlike commercial and open-source systems, REVS offers more detailed metrics, customizable wheel compatibility, seamless blending with common vivarium hardware, integrated data visualizations, and ODC-compatible data export. It also supports flexible analysis across individuals and groups. ConclusionsREVS provides a powerful, scalable tool for granular behavioral phenotyping in rodent studies, enhancing reproducibility and revealing insights into subtle locomotor changes associated with injury, recovery, and intervention. HighlightsO_LIREVS enables detailed analysis of voluntary wheel running in rodents C_LIO_LIThe platform combines low-cost hardware with open-source analysis software C_LIO_LIREVS computes 13 behavioral metrics across daily and bout-level timescales C_LIO_LIWe identified a unique lesion and recovery profile after partial spinal cord injury C_LIO_LIREVS supports ODC-compatible data export for transparency and reuse C_LI

neuroscience↗

bioRxiv2021

Single-Cell Transcriptional Profiling of the Adult Corticospinal Tract Reveals Forelimb and Hindlimb Molecular Specialization

The corticospinal tract (CST) is refractory to repair after CNS trauma, resulting in chronic debilitating functional motor deficits after spinal cord injury. While novel pro-axon growth activators have stimulated plasticity and regeneration of corticospinal neurons (CSNs) after injury, robust functional recovery remains elusive. These repair strategies are sub-optimal in part due to underexplored molecular heterogeneity within the developing and adult CST. In this study, we combine retrograde CST tracing with single-cell RNA sequencing to build a comprehensive atlas of CSN subtypes. By comparing CSNs to non-spinally projecting neurons in layer Vb, we identify pan-CSN markers including Wnt7b. By leveraging retrograde tracing, we are able to compare forelimb and hindlimb projecting CSNs, identifying subtype-specific markers, including Cacng7 and Slc16a2 respectively. These markers are expressed in embryonic and neonatal CSNs and can be used to study early postnatal patterning of the CST. Our results provide molecular insight into the differences between anatomically distinct CSN subtypes and provide a resource for future screening and exploitation of these subtypes to repair the damaged CST after injury and disease.

neuroscience↗

bioRxiv2021

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma.

Failure of CNS neurons to mount a significant intrinsic growth response after trauma results in chronic functional deficits after spinal cord injury. Approaches to identify novel axon growth activators include transcriptional and repressor screening of embryonic cortical and retinal ganglion neurons in vitro. These high throughput approaches have identified several candidates; however, their inability to comprehensively model the adult CNS has resulted in their exploitation in vivo failing to stimulate significant anatomical and functional gains. To identify novel cell autonomous axon growth activators while maintaining CNS complexity, we screened intact adult corticospinal neurons (CSNs) undergoing functional plasticity after unilateral pyramidotomy. RNA-seq of intact sprouting corticospinal tract (CST) axons showed an enrichment of genes in the 3-phosphoinositide degradation pathways, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K (Inpp5k) could enhance CST axon growth in clinical models of CNS trauma. Overexpression of Inpp5k in intact adult CSNs enhanced sprouting of intact CST terminals into the denervated cervical cord after pyramidotomy and cortical stroke lesion. Inpp5k overexpression also stimulated sprouting of CST axons in the cervical cord after acute and chronic severe thoracic spinal contusion. We show that Inpp5k stimulates axon growth by elevating the density of active cofilin in the cytosol of labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. This study identifies Inpp5k as a novel CST growth activator and underscores the veracity of using in vivo transcriptional screening to identify the next generation of cell autonomous factors capable of repairing the damaged CNS. SIGNIFICANCE STATEMENTNeurological recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post trauma. In vitro screening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growth in vivo, concomitant functional recovery remains incomplete. Using transcriptional profiling of intact adult corticospinal tract neurons undergoing functional plasticity, we identified Inpp5k as a novel axon growth activator capable of stimulating CST axon growth after pyramidotomy, stroke and acute and chronic contusion injuries. These data support using in vivo screening approaches to identify novel axon growth activators.

neuroscience↗