Postnatal Serotonin Deficits in Behavioral Pathogenesis: A Novel Genetic Approach

产后血清素缺乏的行为发病机制：一种新的遗传学方法

• 批准号: 8647217
• 负责人: Meredith Sorenson Whitney
• 金额: $ 4.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647217
• 关键词: Address; Adolescence; Adolescent; Adult; Adverse effects; Affect; Aftercare; Aggressive behavior; Animal Model; Antidepressive Agents; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Brain; Chronic; Chronic stress; Corticosterone; Cues; Data; Depression and Suicide; Development; Disease; Embryo; Emotional; Environmental Risk Factor; Enzymes; Exhibits; Feedback; Fright; Gene Expression; Genes; Genetic; Glucocorticoid Receptor; Glycogen Synthase Kinases; Health; Hippocampus (Brain); Human; Hypothalamic structure; Knock-out; Knockout Mice; Maintenance; Major Depressive Disorder; Measures; Mediating; Mental disorders; Modeling; Molecular; Mus; Neurons; Neurotransmitters; Obsessive-Compulsive Disorder; Pathogenesis; Patients; Pituitary-Adrenal System; Plasma; Post-Traumatic Stress Disorders; Predisposition; Prosencephalon; Protein Kinase; Protocols documentation; Regulation; Relapse; Resistance; Role; Serotonin; Signal Transduction; Signaling Molecule; Specificity; Stress; Synapses; System; Tamoxifen; Techniques; Testing; Time; Tryptophan 5-monooxygenase; Viral; behavior test; cohort; conditioned fear; effective therapy; fetal; frontal lobe; innovation; male; mental health related disorder; neuron development; novel; postnatal; postsynaptic; public health relevance; receptor expression; research study; response; social; stress related disorder; tool; transcription factor; young adult

DESCRIPTION (provided by applicant): 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.

描述（由适用提供）：在许多毁灭性和高度普遍的精神疾病的发病机理中暗示了大脑中的异常5-羟色胺（5-HT）信号传导，其中大多数在青少年和年轻的成年中表现出来。虽然5-HT调节抗抑郁药可以帮助许多患者，但由于缓解，抗药性，副作用和缺乏反应，大量患者遭受了痛苦。值得注意的是，关于5-HT信号的变化如何影响行为以及发生这些变化的细节仍未解决，阻碍了更具体和更有效的治疗方法的发展。在某种程度上，这是由于用于改变动物模型中5-HT系统的传统药物技术缺乏特异性和一致性。最近，许多研究已经使用了遗传方法来靶向胎儿5-HT神经元发展和功能所需的转录因子，从而揭示了明显的行为缺陷。尽管这些模型暴露了明显的5-HT缺陷，但它们还影响了许多与5-HT合成无关的其他血清素能功能。自最近发现色氨酸羟化酶2（TPH2）的序列以来，脑5-HT合成中的唯一速率限制酶，敲除研究表明，胚胎5-HT缺陷会导致行为异常。尽管如此，尚不清楚产后5-HT水平的维持对于正常行为至关重要。此外，压力是许多与5-HT相关的疾病的主要环境因素，研究表明，可能涉及5-HT介导的下属辅助 - 垂体 - 肾上腺（HPA）轴的破坏。但是，有关5-HT系统和HPA轴如何相互作用的基本问题仍未得到答复。为了解决这些基本问题，我们开发了一种新型的遗传工具，该工具专门降低了精确时间点的大脑5-HT合成。我们已经产生了表达他莫昔芬（TM）诱导的Creer，Epet：creert2ascend的小鼠，在上升的5-HT神经元中，该神经元预测了参与情感行为的脑电路。我已经用TPH2FL/小鼠越过了该驱动器，以创建TPH2诱导的条件敲除（TPH2CKO）小鼠。令人兴奋的试点数据在我的初步研究中表明，TM治疗TPH2CKO小鼠会导致〜50％上升的5-HT神经元的TPH2表达和5-HT合成的敲除，从而提供自然主义的防御，从而更好地模拟人类疾病。在TM处理的TPH2CKO小鼠中，分子技术将用于量化5-HT和血清素能基因表达的水平。我还将研究产后5-HT缺乏对5-HT相关行为涉及的两种突触后机制的影响，糖原合酶激酶 - （GSK3¿）信号传导和糖皮质激素受体表达。在青少年期间进行TM治疗后，将评估压力和无压力的TPH2CKO小鼠的焦虑，例如行为，恐惧调节和男性间的侵略性等焦虑的变化。这项研究将利用我的创新方法来确定与许多与压力相关的心理健康障碍相关的行为中产后5-HT的重要性。