Wheel Running and Wheel Running and Fluoxetine Antidepressant Fluoxetine Antidepressant
Treatment Have Differential Treatment Have Differential Effects in the Hippocampus Effects in the Hippocampus
and the Spinal Cordand the Spinal Cord
C. Engesser-Cesar, A. J. C. Engesser-Cesar, A. J. Anderson, and C. W. CotmanAnderson, and C. W. Cotman
HypothesisHypothesis
Exercise and antidepressants Exercise and antidepressants independently increase hippocampus independently increase hippocampus (BDNF) and neurogenesis.(BDNF) and neurogenesis.
Effects are on BDNF synergistic Effects are on BDNF synergistic
Background InformationBackground Information
Brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF) is capable of mediating the (BDNF) is capable of mediating the beneficial effects of exercise on brain beneficial effects of exercise on brain plasticity, supports the health and plasticity, supports the health and functioning of glutamatergic functioning of glutamatergic neurons, promotes differentiation, neurons, promotes differentiation, neurite (process) extension, and the neurite (process) extension, and the survival of a variety of neuronal survival of a variety of neuronal populations (1).populations (1).
Exercise ImprovesExercise Improves
Various neurological conditionsVarious neurological conditions• Age-related neurodegenerationAge-related neurodegeneration• DepressionDepression• Alzheimer’s diseaseAlzheimer’s disease• Traumatic brain injury Traumatic brain injury • Spinal cord injurySpinal cord injury
AnimalsAnimals
C57BL/10 female mice (n=112)C57BL/10 female mice (n=112) 2 months old2 months old Acclimatized for 1 week, 7 days of Acclimatized for 1 week, 7 days of
antibiotic adminantibiotic admin Excluded for difficulty with wheel runningExcluded for difficulty with wheel running Food and water ad libitumFood and water ad libitum 12h light/dark cycle12h light/dark cycle Randomly assigned Randomly assigned
AnimalsAnimals
No Wheel Running Wheel Running
Control Control
5mg/kg fluoxetine 5mg/kg fluoxetine
10mg/kg fluoxetine 10mg/kg fluoxetine
25mg/kg fluoxetine 25mg/kg fluoxetine
• 14 animals/group
Methods and MaterialsMethods and Materials
21 days of fluoxetine treatment21 days of fluoxetine treatment• With or without wheel runningWith or without wheel running
Daily i.p. injectionsDaily i.p. injections 6 animals from each group got BrdU 6 animals from each group got BrdU
injections on final 7 daysinjections on final 7 days Killed 24h after last fluoxetine Killed 24h after last fluoxetine
injectioninjection Staggered over 4 days (estrous)Staggered over 4 days (estrous)
FluoxetineFluoxetine
Decreased running distanceDecreased running distance High dose group ran significantly less by High dose group ran significantly less by
the end of the experimentthe end of the experiment Increased weight gainIncreased weight gain
Exercise and FluoxetineExercise and Fluoxetine Together, increase cell proliferation and survival Together, increase cell proliferation and survival
in the hippocampusin the hippocampus
IGF-1: positively linked to hippocampal IGF-1: positively linked to hippocampal neurogenesisneurogenesis• Seen with: Exercise-mediated recovery from traumatic Seen with: Exercise-mediated recovery from traumatic
brain injury brain injury Fluoxetine administration Fluoxetine administration
BDNF: positively linked to hippocampal BDNF: positively linked to hippocampal neurogenesisneurogenesis• is activated more rapidly when used in combination is activated more rapidly when used in combination with exercise and antidepressants (Cotman 2002)with exercise and antidepressants (Cotman 2002)
Spinal CordSpinal Cord
Examined rostral, thoracic, lumbar Examined rostral, thoracic, lumbar Spinal cord IGF-1 protein did not change Spinal cord IGF-1 protein did not change
with wheel running, and decreased with with wheel running, and decreased with fluoxetine (high dose)fluoxetine (high dose)
Cytogenesis also decreased with Cytogenesis also decreased with fluoxetine (dose dependent)fluoxetine (dose dependent)
BDNF did not change in rostral or lumbar BDNF did not change in rostral or lumbar after running or fluoxetine treatmentafter running or fluoxetine treatment
Wheel running and fluoxetine did not Wheel running and fluoxetine did not protect against spinal cord injuryprotect against spinal cord injury
Effects of exercise and fluoxetine Effects of exercise and fluoxetine on spinal cordon spinal cord
IGF-1 protein significantly decreased IGF-1 protein significantly decreased with administration of fluoxetinewith administration of fluoxetine
No neurogenesisNo neurogenesis Decreased cytogenesisDecreased cytogenesis
Spinal Cord InjurySpinal Cord Injury
No benefit for pre-injury exercise for No benefit for pre-injury exercise for SCI recoverySCI recovery
Post-injury exercise and/or fluoxetine Post-injury exercise and/or fluoxetine may be protective may be protective (not explored here)(not explored here)• Trophic factors or cytogenesis could be Trophic factors or cytogenesis could be
a recovery mechanisma recovery mechanism Decreased BrdU in spinal cord ??Decreased BrdU in spinal cord ??
ResultsResults
In the hippocampus fluoxetine In the hippocampus fluoxetine increases BDNF, cytogenesis, and increases BDNF, cytogenesis, and neurogenesisneurogenesis• Dose dependentDose dependent
ResultsResults
BDNF was not induced by exerciseBDNF was not induced by exercise• but increased by fluoxetinebut increased by fluoxetine
Hippocampal IGF-1 protein not affected by Hippocampal IGF-1 protein not affected by fluoxetine, exercise, or bothfluoxetine, exercise, or both
Fluoxetine decreased IGF-1 protein in all Fluoxetine decreased IGF-1 protein in all three regions of the spinal cordthree regions of the spinal cord
ResultsResults
Decreased trend of BrdU positive Decreased trend of BrdU positive cells in exercise animalscells in exercise animals
Fluoxetine also decreases BrdUFluoxetine also decreases BrdU
Decrease in cell proliferationDecrease in cell proliferation
Neurogenesis and CytogenesisNeurogenesis and Cytogenesis
BrdU represents new cells
DCX represents new neurons
b
Wheel running with 25mg/kg fluoxetine dose animal, cytogenesis and neurogenesis
in the hippocampus
Neurogenesis and cytogenesis results
Increased dentate granule cell layer DCX increases, not BrdU with
fluoxetine Fluoxetine and exercise combined no Fluoxetine and exercise combined no
effect on cytogenesis or neurogenesiseffect on cytogenesis or neurogenesis
De Foubert resultsDe Foubert results
Herein, 21 days of wheel running and Herein, 21 days of wheel running and fluoxetine administration increased fluoxetine administration increased BDNF cells in hippocampusBDNF cells in hippocampus
Dependent on length of treatmentDependent on length of treatment
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
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
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
Conclusion
Fluoxetine increased BDNF, cytogenesis, and neurogenesis in the hippocampus
Fluoxetine decreased IGF-1 and cytogenesis in the spinal cord
ReferencesReferences
1. Cotman, C. W., and C. Engesser-Cesar. Exercise 1. Cotman, C. W., and C. Engesser-Cesar. Exercise enhances and protects brain function. enhances and protects brain function. Exerc. Sport Sci RevExerc. Sport Sci Rev. . 30:75-79, 2002.30:75-79, 2002.
2. De Foubert, G., S. L. Carney, C. S. Robinson, E. J. 2. De Foubert, G., S. L. Carney, C. S. Robinson, E. J. Destexhe, R. Tomlinson, C. A. Hicks, T. K. Murray, J. P. Destexhe, R. Tomlinson, C. A. Hicks, T. K. Murray, J. P. Gaillard, C. Deville, V. Xhenseval, C. E. Thomas, M. J. Gaillard, C. Deville, V. Xhenseval, C. E. Thomas, M. J. O’Neill, and T. S. C. Zetterstrom. Fluoxetine-induced change O’Neill, and T. S. C. Zetterstrom. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. varies depending on length of treatment. J. Neurosci. J. Neurosci. 128:597-604, 2004128:597-604, 2004
3. van Praag, H., G. Kempermann, and F. H. Gage. Running 3. van Praag, H., G. Kempermann, and F. H. Gage. Running increases cell proliferation and neurogenesis in the adult increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. mouse dentate gyrus. Nature NeurosciNature Neurosci. 2:266-270, 1999. 2:266-270, 1999