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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Special Emphasis Panel (NSS)
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Winsky, Lois M
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New York State Psychiatric Institute
New York
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Miller, Bradley R; Hen, René (2015) The current state of the neurogenic theory of depression and anxiety. Curr Opin Neurobiol 30:51-8
Wu, Melody V; Hen, René (2014) Functional dissociation of adult-born neurons along the dorsoventral axis of the dentate gyrus. Hippocampus 24:751-61
Mendez-David, Indira; David, Denis J; Darcet, Flavie et al. (2014) Rapid anxiolytic effects of a 5-HTýýý receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology 39:1366-78
Lovett-Barron, Matthew; Kaifosh, Patrick; Kheirbek, Mazen A et al. (2014) Dendritic inhibition in the hippocampus supports fear learning. Science 343:857-63
Donaldson, Zoe R; Piel, David A; Santos, Tabia L et al. (2014) Developmental effects of serotonin 1A autoreceptors on anxiety and social behavior. Neuropsychopharmacology 39:291-302
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
Samuels, Benjamin A; Leonardo, E David; Dranovsky, Alex et al. (2014) Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors. PLoS One 9:e85136
Wu, Melody V; Shamy, Jul Lea; Bedi, Gillinder et al. (2014) Impact of social status and antidepressant treatment on neurogenesis in the baboon hippocampus. Neuropsychopharmacology 39:1861-71
Kheirbek, Mazen A; Hen, René (2014) Add neurons, subtract anxiety. Sci Am 311:62-7
Kheirbek, Mazen A; Drew, Liam J; Burghardt, Nesha S et al. (2013) Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77:955-68

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