Differential effects of exercise and hormone treatment on spinal cord injury-induced changes in micturition and morphology of external urethral sphincter motoneurons

Article type: Research Article

Authors: Hibbard, Emily A.^a | Du, Xiaolong^b | Zhang, Yihong^b | Xu, Xiao-Ming^b | Deng, Lingxiao^{b; *} | Sengelaub, Dale R.^{a; *}

Affiliations: [a] Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA | [b] Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence: [*] Corresponding authors: Dale R. Sengelaub, Psychology Building, Indiana University, 1101 E 10th Street, Bloomington, Indiana 47405, USA. Tel.: + 1 812 855 9149; Fax: + 1 812 855 4691; E-mail: sengelau@indiana.edu and Lingxiao Deng, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Neuroscience Research Building, 320 West 15th Street, Indianapolis, Indiana 46202, USA. Tel.: + 1 317 274 1036; E-mail: dengl@iu.edu.

Abstract: Background:Spinal cord injury (SCI) results in lesions that destroy tissue and spinal tracts, leading to deficits in locomotor and autonomic function. We have previously shown that after SCI, surviving motoneurons innervating hindlimb muscles exhibit extensive dendritic atrophy, which can be attenuated by treadmill training or treatment with gonadal hormones post-injury. We have also shown that following SCI, both exercise and treatment with gonadal hormones improve urinary function. Animals exercised with forced running wheel training show improved urinary function as measured by bladder cystometry and sphincter electromyography, and treatment with gonadal hormones improves voiding patterns as measured by metabolic cage testing. Objective:The objective of the current study was to examine the potential protective effects of exercise or hormone treatment on the structure and function of motoneurons innervating the external urethral sphincter (EUS) after contusive SCI. Methods:Gonadally intact young adult male rats received either a sham or a thoracic contusion injury. Immediately after injury, one cohort of animals was implanted with subcutaneous Silastic capsules filled with estradiol (E) and dihydrotestosterone (D) or left blank; continuous hormone treatment occurred for 4 weeks post-injury. A separate cohort of SCI-animals received either 12 weeks of forced wheel running exercise or no exercise treatment starting two weeks after injury. At the end of treatment, urinary void volume was measured using metabolic cages and EUS motoneurons were labeled with cholera toxin-conjugated horseradish peroxidase, allowing for assessment of dendritic morphology in three dimensions. Results:Locomotor performance was improved in exercised animals after SCI. Void volumes increased after SCI in all animals; void volume was unaffected by treatment with exercise, but was dramatically improved by treatment with E + D. Similar to what we have previously reported for hindlimb motoneurons after SCI, dendritic length of EUS motoneurons was significantly decreased after SCI compared to sham animals. Exercise did not reverse injury-induced atrophy, however E + D treatment significantly protected dendritic length. Conclusions:These results suggest that some aspects of urinary dysfunction after SCI can be improved through treatment with gonadal hormones, potentially through their effects on EUS motoneurons. Moreover, a more comprehensive treatment regime that addresses multiple SCI-induced sequelae, i.e., locomotor and voiding deficits, would include both hormones and exercise.

Keywords: Estradiol, dihydrotestosterone, forced running wheel exercise, metabolic cage, neuroprotection, dendrites

DOI: 10.3233/RNN-241385

Journal: Restorative Neurology and Neuroscience, vol. 42, no. 2, pp. 151-165, 2024