Cellular Mechanisms of Antidepressant Action.

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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. !