Developmental Origins of Affective Disorders

情感障碍的发育起源

• 批准号: 7589009
• 负责人: Mark Sascha Ansorge
• 金额: $ 8.2万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589009
• 关键词: Ablation; Accounting; Adolescent; Adult; Affect; Affective; Agonist; Alleles; Amygdaloid structure; Anatomy; Animals; Anorexia Nervosa; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Area; Autistic Disorder; Award; Axon; Back; Behavior; Behavioral; Brain; Cell Nucleus; Cells; Clozapine; Collaborations; Correlation Studies; Couples; Data; Dendritic Spines; Development; Disease; Disruption; Dorsal; Electric Stimulation; Electrophysiology (science); Emotional; Etiology; Fiber; Fire - disasters; Fluoxetine; Foundations; Functional disorder; Funding Mechanisms; Future; G-Protein-Coupled Receptors; Gases; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Glutamates; Green Fluorescent Proteins; Growth; Growth Factor; Hippocampus (Brain); Human; Hydroxyindoleacetic Acid; Image; Infant; Intrinsic factor; Investigation; Knowledge; Label; Life; Ligands; Link; Magnetic Resonance Imaging; Medial; Mediating; Mental Depression; Modeling; Molecular; Mood Disorders; Morphology; Mus; Neuraxis; Neurons; Neurotic Disorders; Neurotransmitters; Numbers; Obsessive-Compulsive Disorder; Organism; Oxides; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Potassium Channel; Predisposition; Prefrontal Cortex; Pregnancy; Prevention; Principal Investigator; Process; Promoter Regions; Property; Protocols documentation; Publishing; Rate; Regulation; Research; Research Personnel; Safety; Serotonin; Signal Transduction; Slice; Structure; Synapses; System; Testing; Transgenic Mice; Transgenic Organisms; Variant; Ventral Tegmental Area; age group; base; density; design; dopamine system; dorsal raphe nucleus; expectation; fetal; fiber cell; gamma-Aminobutyric Acid; genetic variant; hypothalamic-pituitary-adrenal axis; improved; in vivo; inhibitor/antagonist; insight; nerve supply; neuropsychiatry; postnatal; postsynaptic; programs; promoter; ranpirnase; raphe nuclei; research study; reuptake; serotonin transporter; synaptic function; tool; tool development; translational study

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.

描述（由申请人提供）：5-羟色胺（5-HT）作为神经递质和生长因子发挥作用，以调节脑功能和脑发育。此外，5-HT还与许多神经精神疾病的病因和治疗有关。具体来说，针对5-HT系统的药物;例如选择性5-HT再吸收抑制剂（SSRI）目前被用作抑郁症和焦虑症的一线治疗。此外，一些证据表明，常见的5-羟色胺转运蛋白基因（5 htt）的启动子区的功能多态性与神经精神疾病，如神经质，抑郁症和焦虑症的易感性增加。其他人和我们都假设，这些变异在早期大脑发育过程中对成年人的情感行为产生影响。我们先前已经表明，这种遗传易感性可以在小鼠中通过组成性5 htt消融来建模。此外，我们已经证明，发育5-HTT阻断（PNFLX治疗）模仿遗传5 htt消融的效果，支持发育中断5-HTT功能诱发成人情绪行为变化的假设。然而，关于5-羟色胺如何改变大脑发育的知识，特别是当它与成人焦虑和抑郁相关行为有关时，仍然受到知识上的多重差距的阻碍。 我们提出的实验旨在填补这些空白，并专注于调查早期生活5-HTT阻断中缝功能的发展的影响。第一个目的是研究PNFLX处理的小鼠中缝核神经元的生理学。第二个目的是研究PNFLX处理的小鼠中缝生理学的回路介导的调节。第三个目的是研究PNFLX治疗小鼠的5-羟色胺系统的解剖学。最后，我们的第五个目标将探讨中缝活动在抑郁症和焦虑样行为病因学中的因果关系。这些研究将推进我们对大脑成熟过程中5-羟色胺信号传导如何影响中缝功能的机械理解，因为它与焦虑和抑郁相关的行为有关。我们希望这些新的信息能提供一个更详细的理解，即5-htt的遗传变异如何影响发育，以及如何合谋造成对神经精神疾病的易感性。此外，这些研究与妊娠期间胎儿SSRI暴露的安全性有关。最终，我们的研究结果可能有助于设计更好的预防和治疗抑郁症和焦虑症的策略。