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Unveiling Motor Dysfunction in SORD-Deficient Rats: The Critical Role of Behavioral Tracking in Neuropathy Research

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Introduction

Peripheral neuropathies are complex disorders that significantly impact motor and sensory functions. Recent breakthroughs have identified Sorbitol Dehydrogenase (SORD) deficiency as a leading cause of hereditary motor neuropathy, driven by impaired sorbitol metabolism. While SORD mutations have been linked to motor-predominant neuropathy in humans, the underlying mechanisms remained unclear. The development of a SORD-deficient rat model has provided new insights into disease pathology, but the integration of behavioral tracking technologies adds an invaluable layer of understanding to this model.

Behavioral Tracking in SORD-Deficient Rats: A Key to Understanding Neuropathy

The study of motor dysfunction requires more than molecular and histological analyses; it demands precise, reproducible tracking of behavior. Behavioral tracking provides a functional readout of disease progression, enabling researchers to bridge the gap between microscopic changes and whole-organism outcomes.

1. Behavioral Tests Reveal Early and Progressive Motor Deficits
Behavioral tests conducted on SORD-deficient rats have revealed the onset and progression of motor dysfunction:
 
  • Rotarod Test: This test assesses motor coordination and endurance. SORD-deficient rats exhibited declining performance beginning at 7 months of age, with significantly reduced times to remain on the rod compared to wild-type controls. This decline became more pronounced by 11 and 13 months, indicating progressive motor impairment​(awae079).
  • Narrow Beam Test: This test evaluates balance and fine motor control. By 9 months, SORD-deficient rats took significantly longer to cross the beam, demonstrating coordination deficits that worsened with age​(awae079).
  • Hot Plate Test: Sensory responses were assessed through this test, showing no significant differences in nociceptive reactions between SORD-deficient and wild-type rats. This suggests that motor deficits dominate the phenotype​(awae079).
2. Advanced Gait Analysis Using High-Speed Tracking
Gait abnormalities in SORD-deficient rats were quantified using the MotoRater system, a state-of-the-art tracking platform:
 
  • Joint Angle Measurement: High-speed cameras tracked markers placed on key joints (ankle, knee, hip) to monitor movement during walking. SORD-deficient rats displayed reduced ankle flexion and increased range of motion, reflecting motor weakness.
  • Hip Drop Analysis: Significant increases in hip drop height indicated instability and compensatory gait changes in the hind limbs​(awae079).
  • Longitudinal Analysis: Gait abnormalities emerged around 8 months of age and became more pronounced in older rats, mirroring disease progression.
Behavioral tracking not only quantified deficits but also provided a noninvasive tool for monitoring disease over time, enhancing its value in preclinical research.

Pathophysiological Correlates of Motor Dysfunction

The motor deficits observed in SORD-deficient rats align with molecular and histological findings:
 
  • Sorbitol Accumulation: High sorbitol levels in serum, cerebrospinal fluid (CSF), and nerve tissues were linked to osmotic stress, which disrupted neuronal and myelin integrity. Intriguingly, sorbitol levels in the CSF were 30 times higher than in wild-type rats​(awae079).
  • Histological Abnormalities: Electron microscopy revealed hallmark features, such as ballooned myelin sheaths, axonal degeneration, and thinly myelinated fibers. These findings suggest that osmotic imbalance drives peripheral nerve damage​(awae079).
  • Elevated Neurofilament Light Chain (NfL): As a biomarker of axonal degeneration, increased serum NfL levels correlated with the progressive motor deficits seen in behavioral tracking​(awae079).

Why Behavioral Tracking is Essential

Behavioral tracking technologies play a pivotal role in neuropathy research, offering several advantages:
 
  • Precision and Sensitivity: Advanced systems like MotoRater detect subtle deficits that might be overlooked in traditional assessments.
  • Bridging Scales: By linking molecular changes to whole-organism behavior, these tools provide a comprehensive view of disease mechanisms.
  • Therapeutic Testing: Behavioral metrics, such as rotarod performance and gait parameters, serve as objective endpoints for evaluating potential therapies like aldose reductase inhibitors or gene-editing strategies.

Translational Implications for SORD Neuropathy

The integration of behavioral tracking with biochemical and histological analyses in SORD-deficient rats underscores the potential for this model to:
 
  1. Enhance Early Detection: Subtle gait changes could serve as early indicators of motor neuropathy, guiding timely intervention.
  2. Refine Biomarkers: The correlation of behavioral deficits with NfL and sorbitol levels strengthens their utility as diagnostic and prognostic biomarkers.
  3. Advance Preclinical Trials: Objective behavioral endpoints improve the evaluation of novel therapies, accelerating the translation of research findings to clinical applications.

Conclusion

The SORD-deficient rat model represents a significant step forward in understanding hereditary motor neuropathies. Behavioral tracking adds an indispensable dimension to this model, transforming it from a molecular and histological tool into a powerful platform for studying functional outcomes and testing therapies. For researchers exploring SORD neuropathy or related disorders, embracing behavioral tracking technologies will be critical for unraveling disease mechanisms and advancing treatments.

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Author:

Louise Corscadden, PhD

Dr Louise Corscadden acts as Conduct Science’s Director of Science and Development and Academic Technology Transfer. Her background is in genetics, microbiology, neuroscience, and climate chemistry.

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