An understanding of the mechanisms of treatments for depression and other chronic neurodegenerative processes is an essential goal. Chronic, recurrent depression involves hippocampal atrophy, which can result from chronic stress. Chronic antidepressant treatment restores neurotrophin (BDNF) expression. During our preliminary funding period, we demonstrated that the enhancement of hippocampai BDNF expression resulting from antidepressant treatment is enhanced and accelerated by exercise. We have found evidence, at the transcriptional level, for overlap and synergy between these two interventions, and have demonstrated, using systemic lesions, receptor blockade and neurotransmitter-selective antidepressants, that the noradrenergic system is essential for the observed BDNF changes. Considering the essential role of BDNF for neuronal maintenance and plasticity, our results suggest that exercise may enhance antidepressant treatment response, and repair neuronal degeneration brought about by stress. We now wish to test the hypothesis that exercise and antidepressant treatment converge upon intracellular signaling pathways associated with neuronal survival and plasticity in the hippocampus. Our preliminary evidence suggests that exercise activates the cell survival-enhancing phosphatidylinositol-3 kinase and nitric oxide signaling pathways, in whole animal and hippocampal cell culture models, we will assess the activation of several signaling molecules along these intracellular pathways, and specifically test their involvement in the enhancement of hippocampal BDNF expression following exercise, antidepressant treatment, and noradrenergic activation. We will also test the involvement of other specific survival-promoting pathways (such as cAMP and calcium-mediated) that can be activated by exercise or antidepressant, and where convergence of these two interventions might be demonstrated. With the currently proposed experiments, we also wish to test the hypothesis that our combined interventions will repair stress-induced impairments in hippocampal function (spatial learning deficits), as well as damage to neuronal cytoarchitecture following stress. Our experiments will yield important information about the intracellular, cooperative mechanisms of improved treatment response resulting from exercise. Knowledge about the mechanisms responsible for the enhancement of antidepressant response will inform the development of novel, more efficacious and rapid treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059776-11
Application #
7433885
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Nadler, Laurie S
Project Start
1999-04-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
11
Fiscal Year
2008
Total Cost
$279,939
Indirect Cost
Name
California State University Los Angeles
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066697590
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Chen, Michael J; Russo-Neustadt, Amelia A (2009) Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus 19:962-72
Arunrut, Teda; Alejandre, Hilda; Chen, Michael et al. (2009) Differential behavioral and neurochemical effects of exercise, reboxetine and citalopram with the forced swim test. Life Sci 84:584-9
Haack, Danielle; Luu, Henry; Cho, Jaehoon et al. (2008) Exercise reverses chronic stress-induced Bax oligomer formation in the cerebral cortex. Neurosci Lett 438:290-4
Chen, Michael J; Russo-Neustadt, Amelia A (2007) Nitric oxide signaling participates in norepinephrine-induced activity of neuronal intracellular survival pathways. Life Sci 81:1280-90
Chen, Michael J; Russo-Neustadt, Amelia A (2007) Running exercise- and antidepressant-induced increases in growth and survival-associated signaling molecules are IGF-dependent. Growth Factors 25:118-31
Chen, Michael J; Ivy, Autumn S; Russo-Neustadt, Amelia A (2006) Nitric oxide synthesis is required for exercise-induced increases in hippocampal BDNF and phosphatidylinositol 3' kinase expression. Brain Res Bull 68:257-68
Chen, Michael J; Russo-Neustadt, Amelia A (2005) Exercise activates the phosphatidylinositol 3-kinase pathway. Brain Res Mol Brain Res 135:181-93
Russo-Neustadt, Amelia A; Alejandre, Hilda; Garcia, Celithelma et al. (2004) Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise. Neuropsychopharmacology 29:2189-99
Garza, Antonio A; Ha, Tony G; Garcia, Celithelma et al. (2004) Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav 77:209-20
Garcia, C; Chen, M J; Garza, A A et al. (2003) The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity. Neuroscience 119:721-32

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