Most antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) increase serotonin levels throughout the brain. However it is still unclear which specific circuits mediate the behavioral effects of these compounds. We have shown that mice lacking the serotonin 1A receptor (5-HTIA) specifically in the dentate gyrus do not respond to SSRIs in several animal models of anxiety and depression (Samuels et al., 2012, appended paper). In a separate set of experiments we have shown that neurogenesis in the dentate gyrus is required for some but not all behavioral effects of antidepressants (David et al., 2009). These two independent lines of evidence point to the dentate gyrus as playing an important role in the behavioral effects of antidepressants. These findings are surprising because the dentate gyrus (DG) ofthe hippocampus has been extensively studied for its role in learning and memory and specifically in encoding new information and in disambiguating similar informations, a process termed pattern separation. However the role of this part ofthe hippocampus in anxiety and depression-related behaviors is poorly understood. In the current proposal we propose to reconcile these two seemingly unrelated functions ofthe DG by testing the general hypothesis that the functions ofthe DG are distinct along its dorso-ventral axis with the dorsal part being involved in neutral pattern separation while the ventral part is involved in emotional pattern separation, a process that is often impaired in mood and anxiety disorders. These studies will paveithe way for novel strategies aimed at modulating the excitability of the ventral DG for the treatment of anxiety and mood disorders.

Public Health Relevance

Over 20% of adult Americans are, at some point, diagnosed with either mood or anxiety disorders, with enormous personal, societal and financial costs. The most common treatments for these disorders are the selective serotonin reuptake inhibitors (SSRIs). However, only 25-50% of patients achieve remission. Therefore, there is a considerable need for new therapies. This proposal will lay the groundwork for a totally novel treatment strateav for these disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Winsky, Lois M
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New York State Psychiatric Institute
New York
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Anacker, Christoph; Hen, René (2017) Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat Rev Neurosci 18:335-346
Samuels, Benjamin Adam; Mendez-David, Indira; Faye, Charlène et al. (2016) Serotonin 1A and Serotonin 4 Receptors: Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants. Neuroscientist 22:26-45
Brachman, Rebecca A; McGowan, Josephine C; Perusini, Jennifer N et al. (2016) Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. Biol Psychiatry 79:776-86
Nautiyal, Katherine M; Tritschler, Laurent; Ahmari, Susanne E et al. (2016) A Lack of Serotonin 1B Autoreceptors Results in Decreased Anxiety and Depression-Related Behaviors. Neuropsychopharmacology 41:2941-2950
Tannenholz, Lindsay; Hen, René; Kheirbek, Mazen A (2016) GluN2B-Containg NMDA Receptors on Adult-Born Granule Cells Contribute to the Antidepressant Action of Fluoxetine. Front Neurosci 10:242
Drew, Liam J; Kheirbek, Mazen A; Luna, Victor M et al. (2016) Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus 26:763-78
Danielson, Nathan B; Kaifosh, Patrick; Zaremba, Jeffrey D et al. (2016) Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding. Neuron 90:101-12
Wu, Melody V; Sahay, Amar; Duman, Ronald S et al. (2015) Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus. Cold Spring Harb Perspect Biol 7:a018978
Park, Eun Hye; Burghardt, Nesha S; Dvorak, Dino et al. (2015) Experience-Dependent Regulation of Dentate Gyrus Excitability by Adult-Born Granule Cells. J Neurosci 35:11656-66
Miller, Bradley R; Hen, René (2015) The current state of the neurogenic theory of depression and anxiety. Curr Opin Neurobiol 30:51-8

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