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Wheel Running and Fluoxetine Antidepressant Treatment Have Differential Effects in the Hippocampus and the Spinal Cord

Hypothesis. Exercise and antidepressants independently increase hippocampus (BDNF) and neurogenesis.Effects are on BDNF synergistic . Background Information. Brain-derived neurotrophic factor (BDNF) is capable of mediating the beneficial effects of exercise on brain plasticity, supports the health

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Wheel Running and Fluoxetine Antidepressant Treatment Have Differential Effects in the Hippocampus and the Spinal Cord

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    1. Wheel Running and Fluoxetine Antidepressant Treatment Have Differential Effects in the Hippocampus and the Spinal Cord C. Engesser-Cesar, A. J. Anderson, and C. W. Cotman

    2. Hypothesis Exercise and antidepressants independently increase hippocampus (BDNF) and neurogenesis. Effects are on BDNF synergistic

    3. Background Information Brain-derived neurotrophic factor (BDNF) is capable of mediating the beneficial effects of exercise on brain plasticity, supports the health and functioning of glutamatergic neurons, promotes differentiation, neurite (process) extension, and the survival of a variety of neuronal populations (1).

    4. Exercise Improves Various neurological conditions Age-related neurodegeneration Depression Alzheimers disease Traumatic brain injury Spinal cord injury

    5. Animals C57BL/10 female mice (n=112) 2 months old Acclimatized for 1 week, 7 days of antibiotic admin Excluded for difficulty with wheel running Food and water ad libitum 12h light/dark cycle Randomly assigned

    6. Animals

    7. Methods and Materials

    8. Methods and Materials 21 days of fluoxetine treatment With or without wheel running Daily i.p. injections 6 animals from each group got BrdU injections on final 7 days Killed 24h after last fluoxetine injection Staggered over 4 days (estrous)

    9. Fluoxetine Decreased running distance High dose group ran significantly less by the end of the experiment Increased weight gain

    10. Exercise and Fluoxetine Together, increase cell proliferation and survival in the hippocampus IGF-1: positively linked to hippocampal neurogenesis Seen with: Exercise-mediated recovery from traumatic brain injury Fluoxetine administration BDNF: positively linked to hippocampal neurogenesis is activated more rapidly when used in combination with exercise and antidepressants (Cotman 2002)

    11. Spinal Cord Examined rostral, thoracic, lumbar Spinal cord IGF-1 protein did not change with wheel running, and decreased with fluoxetine (high dose) Cytogenesis also decreased with fluoxetine (dose dependent) BDNF did not change in rostral or lumbar after running or fluoxetine treatment Wheel running and fluoxetine did not protect against spinal cord injury

    12. Rostral Cord

    13. Lumbar Cord

    14. Thoracic Cord

    15. Effects of exercise and fluoxetine on spinal cord IGF-1 protein significantly decreased with administration of fluoxetine No neurogenesis Decreased cytogenesis

    16. Spinal Cord Injury No benefit for pre-injury exercise for SCI recovery Post-injury exercise and/or fluoxetine may be protective (not explored here) Trophic factors or cytogenesis could be a recovery mechanism Decreased BrdU in spinal cord ??

    17. Results In the hippocampus fluoxetine increases BDNF, cytogenesis, and neurogenesis Dose dependent

    18. Results BDNF was not induced by exercise but increased by fluoxetine Hippocampal IGF-1 protein not affected by fluoxetine, exercise, or both Fluoxetine decreased IGF-1 protein in all three regions of the spinal cord

    19. Results Decreased trend of BrdU positive cells in exercise animals Fluoxetine also decreases BrdU Decrease in cell proliferation BrdU positive means there was neurogenesis present, DCX positive cells means there was cytogenesis presentBrdU positive means there was neurogenesis present, DCX positive cells means there was cytogenesis present

    20. BDNF and Serum IGF1 Exercise alone had little effect on increasing BDNFExercise alone had little effect on increasing BDNF

    21. IGF1 hippocampal results

    22. Neurogenesis and Cytogenesis High dose fluoxetine increases BrdU cells by percentage, and DCX positive cells by percentage, wheel running had little effect on BrdU or DCX cells.High dose fluoxetine increases BrdU cells by percentage, and DCX positive cells by percentage, wheel running had little effect on BrdU or DCX cells.

    25. Neurogenesis and cytogenesis results Increased dentate granule cell layer DCX increases, not BrdU with fluoxetine Fluoxetine and exercise combined no effect on cytogenesis or neurogenesis

    26. Cell numerical density

    27. De Foubert Graph Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF

    28. De Foubert Graph Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF

    29. De Foubert Graph Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF Decrease in BDNF after 4 days of running and fluoxetine administration, increase in BDNF after 7 days of running and fluox admin, after 14 days of running and fluox admin large increase in hippocampl BDNF

    30. De Foubert results Herein, 21 days of wheel running and fluoxetine administration increased BDNF cells in hippocampus Dependent on length of treatment

    31. Discussion Exercise or fluoxetine did not increase IGF-1 as previously seen No change in BDNF protein with exercise in female mice Gender, strain, or amount of exercise could effect BDNF protein High dose fluoxetine increased hippocampal BDNF protein

    32. Discussion Wheel running did not effect BDNF in hippocampus Exercise and fluoxetine may use different mechanisms for BDNF increase No change in IGF-1 in hippocampus High dose fluoxetine increased cytogenesis and neurogenesis in hippocampus

    33. Discussion No increase in BDNF in spinal cord High dose fluoxetine decreased IGF-1 No increase cytogenesis/neurogenesis in spinal cord with any treatment No pre-injury exercise helped SCI

    34. Conclusion Fluoxetine increased BDNF, cytogenesis, and neurogenesis in the hippocampus Fluoxetine decreased IGF-1 and cytogenesis in the spinal cord

    35. References 1. Cotman, C. W., and C. Engesser-Cesar. Exercise enhances and protects brain function. Exerc. Sport Sci Rev. 30:75-79, 2002. 2. De Foubert, G., S. L. Carney, C. S. Robinson, E. J. Destexhe, R. Tomlinson, C. A. Hicks, T. K. Murray, J. P. Gaillard, C. Deville, V. Xhenseval, C. E. Thomas, M. J. ONeill, and T. S. C. Zetterstrom. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. J. Neurosci. 128:597-604, 2004 3. van Praag, H., G. Kempermann, and F. H. Gage. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neurosci. 2:266-270, 1999

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