Abnormal serotonin (5-HT) signaling in the brain has been implicated in the pathogenesis of many devastating and highly prevalent psychiatric disorders, the majority of which manifest in adolescence and young adulthood. While 5-HT modulating antidepressants help many patients, a significant percentage of patients suffer due to relapse, resistance, side effects, and lack of response. Significantly, the details of how alterations in 5-HT signaling affect behavior and when those alterations occur are still unresolved, impeding the development of more specific and effective treatments. In part, this is due to a lack of specificity and consistency in traditional pharmacological techniques used to alter the 5-HT system in animal models. More recently, many studies have employed genetic approaches to target transcription factors required for fetal 5-HT neuron development and function, revealing significant behavioral deficits. While those models exhibited significant 5-HT deficiencies, they also affected many other serotonergic functions not related to 5-HT synthesis. Since the recent discovery of the sequence of tryptophan hydroxylase 2 (Tph2), the sole rate- limiting enzyme in brain 5-HT synthesis, knockout studies have shown that embryonic 5-HT deficiencies can cause behavioral abnormalities. Still, it is not yet clear if maintenance of postnatal 5-HT levels is critical for normal behavior. Additionally, stress is a major environmenta factor in many 5-HT-related disorders, and studies have suggested that disruption of 5-HT-mediated regulation of the hypothathlamic-pituitary-adrenal (HPA) axis may be involved. However, fundamental questions about how the 5-HT system and the HPA axis interact remain unanswered. To address these fundamental questions, we have developed a novel genetic tool that specifically decreases brain 5-HT synthesis at precise time points. We have generated mice that express a tamoxifen (TM)-inducible CreER, ePet:CreERT2ascend, in ascending 5-HT neurons, which project to forebrain circuitry involved in emotional behaviors. I have crossed this driver with Tph2fl/? mice to create Tph2 inducible conditional knockout (Tph2CKO) mice. Exciting pilot data in my initial studies demonstrate that TM treatment of Tph2CKO mice results in knockout of Tph2 expression and 5-HT synthesis in ~50% of ascending 5-HT neurons, providing a naturalistic deficit that will better model human disorders. In TM-treated Tph2CKO mice, molecular techniques will be used to quantify the level of 5-HT and serotonergic gene expression. I will also investigate the effect of postnatal 5-HT deficiency on two post-synaptic mechanisms involved in 5-HT-related behaviors, glycogen synthase kinase-? (GSK3 ?) signaling and glucocorticoid receptor expression. Following TM treatment during adolescence, stressed and unstressed Tph2CKO mice will be evaluated for changes in anxiety like behaviors, fear conditioning, and inter-male aggression. This study will take advantage of my innovative approaches to determine the importance, specifically, of postnatal 5-HT in behaviors that are relevant to many stress-related mental health disorders.
While decreased serotonin (5-HT) signaling in the brain has been implicated in many prevalent, devastating stress-related psychiatric disorders, exactly how and when 5-HT signaling is altered in these disorders is still unknown, impeding the development of more specific and effective treatments. This study will use a new genetic approach to specifically decrease brain 5-HT levels in adolescent mice, and the mice will be evaluated using a variety of behavioral tests relevant to human stress-related disorders. This will help to determine if adolescent decreases in 5-HT levels result in abnormal behaviors and responses to stress, providing information critical for defining when 5-HT is needed for normal emotional health.