Developmental Origins of Affective Disorders

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DESCRIPTION (provided by applicant): Serotonin (5-HT) functions both as a neurotransmitter and as a growth factor to modulate brain function and brain development. In addition, 5-HT has been implicated in the etiology and treatment of numerous neuropsychiatric disorders. Specifically, drugs which target the 5-HT system; such as selective 5-HT reuptake inhibitors (SSRIs) are currently used as the first-line treatment for depression and anxiety disorders. Furthermore, several lines of evidence suggest that commonly occurring functional polymorphisms in the promoter region of the serotonin transporter gene (5htt) are associated with increased susceptibility to neuropsychiatric disorders such as neuroticism, depression, and anxiety. Others and we have hypothesized that these variants exert their effects on adult emotional behavior during early brain development. We have previously shown that this genetic predisposition can be modeled in mice by constitutive 5htt ablation. Furthermore, we have demonstrated that developmental 5-HTT blockade (PNFLX treatment) mimics the effect of genetic 5htt ablation, supporting the hypothesis that developmental disruption of 5-HTT function elicits changes in adult emotional behavior. Yet, knowledge of how serotonin acts to alter brain development, especially as it relates to adult anxiety and depression-related behaviors, is still hampered by multiple gaps in knowledge. Our proposed experiments aim at filling these gaps and focus on investigating the effects of early-life 5-HTT blockade on the development of raphe function. The first aim will investigate the physiology of raphe serotonergic neurons in PNFLX treated mice. The second aim will investigate circuitry mediated modulation of raphe physiology in PNFLX treated mice. The third aim will investigate the anatomical in the serotonin system of PNFLX treated mice. Finally, our fifth aim will investigate the causal involvement of raphe activity in the etiology of depression and anxiety-like behaviors. These studies will advance our mechanistic understanding of how serotonin signaling during brain maturation affects raphe function as it relates to anxiety- and depression-related behaviors. We expect that this new information will provide a more detailed understanding of how genetic variants of 5-htt influence development and conspire to create vulnerability to neuropsychiatric disorders. In addition, these studies have relevance to the safety of fetal SSRI exposure during pregnancy. Ultimately our findings might help in devising improved prevention and treatment strategies for depression and anxiety disorders.