Depression and anxiety disorders are debilitating illnesses that affect more than 350 million people wordwide. The most common treatments for these disorders are SSRIs (selective serotonin reuptake inhibitors) which block the serotonin transporter and thereby increase serotonin levels in many brain regions. However, about 50% of patients who take SSRIs do not fully respond and among those who respond a significant fraction experiences various side effects such as sexual dysfunction. In addition, SSRIs have a delayed onset of therapeutic efficacy of several weeks. There is therefore a considerable need for better and faster acting antidepressants. One way to develop novel antidepressants is to understand how SSRIs work and why they take so long to be effective and then to target directly the underlying mechanisms. One of the dominant hypothesis in this field is that downstream of the increase in serotonin elicited by SSRIs there are a number of growth related changes such as an increase in hippocampal neurogenesis and a rewiring of limbic circuits that are responsible for the delayed onset of efficacy of SSRIs. We have discovered several lines of evidence pointing to the ventral hippocampus and specifically the ventral dentate gyrus (DG) as being critical for many of the antidepressant and anxiolytic-like effects of chronic SSRIs in animal models. In the current application, we propose to build on these results to understand how a chronic exposure to SSRIs modifies the activity of the ventral DG and consequently of the ventral hippocampus and the limbic structures it influences, to generate an antidepressant response. To achieve this goal, we propose to assess the activity of the ventral hippocampus in response to chronic SSRIs with calcium imaging and miniscopes in freely moving mice. Our overarching hypothesis is that the concerted action of SSRIs on young and mature granule cells of the ventral DG results in a decrease in the activity of the DG and consequently a decrease in the activity of ?anxiety cells? located in the ventral portion of CA1 and projecting to the limbic system, ultimately resulting in antidepressant and anxiolytic-like effects. These studies will therefore enable us to identify changes in the function of the ventral hippocampus that are produced by a chronic treatment with SSRIs and that are critical for the antidepressant response in animal models. Such knowledge will in turn inform novel therapeutic approaches aimed at targeting directly specific cells in the ventral hippocampus in order to develop faster and more efficacious antidepressants. !

Public Health Relevance

SSRIs are currently the first line treatment for depression and anxiety disorders but they work slowly and in only about 50% of patients. We propose here to study the activity of select populations of brain cells that are critical for their action and that are located in a brain region called the ventral hippocampus. Our hope is to identify novel targets that may lead to better antidepressant therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH068542-16
Application #
9446677
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2003-05-07
Project End
2022-11-30
Budget Start
2018-02-01
Budget End
2018-11-30
Support Year
16
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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
Denny, Christine A; Burghardt, Nesha S; Schachter, Daniel M et al. (2012) 4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning. Hippocampus 22:1188-201
Kheirbek, Mazen A; Klemenhagen, Kristen C; Sahay, Amar et al. (2012) Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci 15:1613-20

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