PREVENTION OF DENDRITIC ATROPHY AFTER MOTONEURON INJURY

Summary

Principal Investigator: DALE SENGELAUB
Abstract: Neurodegenerative diseases or nerve injury can result in the loss of spinal motoneurons. However, remaining motoneurons after such insults show a variety of morphological and functional changes. As a consequence of both the loss of some motoneurons and the secondary changes in other, remaining motoneurons, functional restoration is poor, and the time course of recovery is protracted at best. The development of animal models, for example involving direct spinal cord damage or peripheral nerve injury, have begun to yield clues to both the mechanisms involved in motoneuron pathology and potential therapeutic approaches. Our work will concentrate on motoneuron dendrites, which are essential for the reception and integration of information. Dendrites in motoneurons atrophy after nerve injury or the death of neighboring motoneurons, and preventing that atrophy, or improving its recovery, in motoneurons that survive the initial insult will have a major impact on the restoration of spinal function. We have begun to develop two models in the adult rat spinal cord, utilizing induced motoneuron death or peripheral nerve cuts that will allow us to examine potential ways of preventing, or accelerating recovery from, dendritic atrophy in remaining motoneurons. In our first model, we found that the death of neighboring motoneurons causes the dendritic arbor of the remaining motoneurons to atrophy, but that manipulation of steroid hormones, specifically testosterone, can prevent or reverse that atrophy. Using morphological methods, we will determine if there is a dose/effect relationship for testosterone and dendritic protection, and if so, establish the minimum amount of testosterone required. We will also test the degree of functional recovery produced by these manipulations using electrophysiological methods. Using morphological methods, we will determine if there are critical temporal limits to the therapeutic window for protection from dendritic atrophy, and whether androgen prevents or accelerates recovery from dendritic atrophy. In our second model, we found an interactive effect of testosterone with brain-derived neurotrophic factor (BDNF) in preventing dendritic atrophy after cutting peripheral motor nerves. We will test whether the expression of BDNF in muscle or motoneurons, or its receptors, could be regulated by androgens, utilizing in situ hybridization and immunohistochemical techniques Together, results from studies using these two models will be informative about the therapeutic role for steroid hormones in treating spinal cord disease or nerve injury.
Funding Period: 2005-07-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems
    T Verhovshek
    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute and Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neuroscience 239:103-14. 2013
  2. pmc Overexpression of androgen receptors in target musculature confers androgen sensitivity to motoneuron dendrites
    Anna L Huguenard
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 152:639-50. 2011
  3. pmc Trophic effects of brain-derived neurotrophic factor blockade in an androgen-sensitive neuromuscular system
    Tom Verhovshek
    Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 151:5337-48. 2010
  4. pmc Maternal care effects on the development of a sexually dimorphic motor system: the role of spinal oxytocin
    Kathryn M Lenz
    Department of Physiology and Program in Neuroscience, University of Maryland Baltimore, MD 21201, USA
    Horm Behav 58:575-81. 2010
  5. pmc Neuroprotective effects of testosterone on dendritic morphology following partial motoneuron depletion: efficacy in female rats
    Randall E Wilson
    Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States
    Neurosci Lett 465:123-7. 2009
  6. pmc Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature
    Tom Verhovshek
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 151:253-61. 2010
  7. pmc Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons
    Keith N Fargo
    Research and Development Service, Edward Hines, JR VA Hospital, Hines, Illinois 60141, USA
    Dev Neurobiol 69:825-35. 2009
  8. pmc Maternal care effects on SNB motoneuron development: the mediating role of sensory afferent distribution and activity
    Kathryn M Lenz
    Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA
    Dev Neurobiol 69:603-15. 2009
  9. pmc Neuroprotective actions of androgens on motoneurons
    Keith N Fargo
    Research and Development Service, Edward Hines, JR VA Hospital, Hines, IL, USA
    Front Neuroendocrinol 30:130-41. 2009
  10. pmc Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons
    Christine M Little
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    J Comp Neurol 512:359-72. 2009

Scientific Experts

  • DALE SENGELAUB
  • Keith N Fargo
  • Kathryn M Lenz
  • Tom Verhovshek
  • T Verhovshek
  • Anna L Huguenard
  • Kellie D Coons
  • Randall E Wilson
  • Christine M Little
  • M C Osborne
  • L M Rudolph
  • Shannon M Fernando
  • D Ashley Monks
  • Mark C Osborne
  • Yi Cai

Detail Information

Publications13

  1. pmc Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems
    T Verhovshek
    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute and Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neuroscience 239:103-14. 2013
    ....
  2. pmc Overexpression of androgen receptors in target musculature confers androgen sensitivity to motoneuron dendrites
    Anna L Huguenard
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 152:639-50. 2011
    ..Thus, it appears that the androgen sensitivity of motoneuron dendrites is conferred indirectly via the enrichment of ARs in the musculature...
  3. pmc Trophic effects of brain-derived neurotrophic factor blockade in an androgen-sensitive neuromuscular system
    Tom Verhovshek
    Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 151:5337-48. 2010
    ..These results may have relevance to therapeutic approaches to the treatment of neurodegenerative disease or myopathies...
  4. pmc Maternal care effects on the development of a sexually dimorphic motor system: the role of spinal oxytocin
    Kathryn M Lenz
    Department of Physiology and Program in Neuroscience, University of Maryland Baltimore, MD 21201, USA
    Horm Behav 58:575-81. 2010
    ..Together, these results suggest that oxytocin afferent activity may contribute to the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior...
  5. pmc Neuroprotective effects of testosterone on dendritic morphology following partial motoneuron depletion: efficacy in female rats
    Randall E Wilson
    Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, United States
    Neurosci Lett 465:123-7. 2009
    ..These findings suggest that testosterone has neuroprotective effects on morphology in both males and females, further supporting a role for testosterone as a neurotherapeutic agent in the injured nervous system...
  6. pmc Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature
    Tom Verhovshek
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Endocrinology 151:253-61. 2010
    ..More importantly, by examining both the motoneurons and the muscles they innervate, these results demonstrate that within a neural system, BDNF levels in different components are differentially affected by androgen manipulation...
  7. pmc Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons
    Keith N Fargo
    Research and Development Service, Edward Hines, JR VA Hospital, Hines, Illinois 60141, USA
    Dev Neurobiol 69:825-35. 2009
    ..These data provide a functional correlate to the known protective effects of testosterone treatment on the morphology of these motoneurons, and further support a role for testosterone as a therapeutic agent in the injured nervous system...
  8. pmc Maternal care effects on SNB motoneuron development: the mediating role of sensory afferent distribution and activity
    Kathryn M Lenz
    Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN 47405, USA
    Dev Neurobiol 69:603-15. 2009
    ..Together, these results suggest that perineal sensory afferent activity mediates the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior...
  9. pmc Neuroprotective actions of androgens on motoneurons
    Keith N Fargo
    Research and Development Service, Edward Hines, JR VA Hospital, Hines, IL, USA
    Front Neuroendocrinol 30:130-41. 2009
    ..Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from motoneuron injury...
  10. pmc Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons
    Christine M Little
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    J Comp Neurol 512:359-72. 2009
    ....
  11. pmc The spinal nucleus of the bulbocavernosus: firsts in androgen-dependent neural sex differences
    Dale R Sengelaub
    Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405, USA
    Horm Behav 53:596-612. 2008
    ..We also describe new data on neurotherapeutic effects of androgens on SNB motoneurons after injury in adulthood...
  12. pmc Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons
    Keith N Fargo
    Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA
    Dev Neurobiol 67:1094-106. 2007
    ..These results indicate that the neuroprotective effect of testosterone on the morphology of SNB motoneurons following partial motoneuron depletion is an androgen effect rather than an estrogen effect...
  13. ncbi Androgen regulates trkB immunolabeling in spinal motoneurons
    M C Osborne
    Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, Indiana 47405, USA
    J Neurosci Res 85:303-9. 2007
    ..This finding suggests that the combinatorial effect of BDNF and testosterone in the maintenance of motoneurons could occur at least in part through an androgen-mediated expression of the BDNF receptor...