The current proposal is aimed at understanding the mode of action of medications that are currently used to treat a variety of depression and anxiety-related disorders. Although selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants and anxiolytics, their mechanisms of action, and particularly the reason for their delayed (4-6 weeks) onset of therapeutic effects, are largely unknown. The general hypothesis that we are proposing to test is that the increased hippocampal neurogenesis elicited by chronic antidepressants contributes to the behavioral effects of these drugs. We, and others, have shown that various chronic antidepressant treatments result in an increase in neurogenesis in the dentate gyrus of the hippocampus. We have also shown that a chronic antidepressant treatment decreases certain anxiety-related behavioral responses. Finally, we have developed two distinct manipulations (a genetic one and radiological one) that disrupt antidepressant-induced hippocampal neurogenesis and also suppress antidepressant-induced behavioral responses. The genetic manipulation is a deletion of the gene encoding the 5-HT1A receptor; the resulting knockout mice are insensitive to the effects of SSRIs such as fluoxetine on both neurogenesis and behavior. The radiological manipulation consists of an X-irradiation of an area of the mouse brain containing the hippocampus; such a treatment prevents the effect of fluoxetine on both neurogenesis and behavior. These two sets of findings strongly suggest that the induction of neurogenesis elicited by fluoxetine in the hippocampus contributes to the behavioral effects of fluoxetine. The following experiments are designed to test this hypothesis and to establish the functional significance of adult hippocampal neurogenesis. 1. We will test the hypothesis that activation of hippocampal 5-HTIA receptors mediates the effects of fiuoxetine on neurogenesis and behavior. To accomplish this goal, we will construct """"""""rescue"""""""" mice that express 5-HT1A receptors only in the hippocampus. 2. We will test the hypothesis that an ablation of neuronal progenitors will suppress the effects of fluoxetine. Such a finding would open new therapeutic avenues based on the stimulation of hippocampal neurogenesis, for the treatment of depression-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068542-05
Application #
7218624
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Winsky, Lois M
Project Start
2003-05-07
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$337,826
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Jimenez, Jessica C; Su, Katy; Goldberg, Alexander R et al. (2018) Anxiety Cells in a Hippocampal-Hypothalamic Circuit. Neuron 97:670-683.e6
Anacker, Christoph; Luna, Victor M; Stevens, Gregory S et al. (2018) Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature 559:98-102
Adam Samuels, Benjamin; Leonardo, E David; Hen, René (2015) Hippocampal subfields and major depressive disorder. Biol Psychiatry 77:210-211
Samuels, Benjamin Adam; Anacker, Christoph; Hu, Alice et al. (2015) 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response. Nat Neurosci 18:1606-16
Denny, Christine A; Kheirbek, Mazen A; Alba, Eva L et al. (2014) Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83:189-201
Ikrar, Taruna; Guo, Nannan; He, Kaiwen et al. (2013) Adult neurogenesis modifies excitability of the dentate gyrus. Front Neural Circuits 7:204
Burghardt, Nesha S; Park, Eun Hye; Hen, René et al. (2012) Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus 22:1795-808
Glinka, Meredith E; Samuels, Benjamin A; Diodato, Assunta et al. (2012) Olfactory deficits cause anxiety-like behaviors in mice. J Neurosci 32:6718-25
Tanaka, Kenji F; Samuels, Benjamin Adam; Hen, Rene (2012) Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos Trans R Soc Lond B Biol Sci 367:2395-401
Kheirbek, Mazen A; Tannenholz, Lindsay; Hen, René (2012) NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J Neurosci 32:8696-702

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