Developmental Origins of Affective Disorders

情感障碍的发育起源

• 批准号: 8142043
• 负责人: Mark Sascha Ansorge
• 金额: $ 24.65万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142043
• 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; Dorsal; Electric Stimulation; Electrophysiology (science); Emotional; Etiology; Fiber; 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; 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; Methodology; Modeling; Molecular; Mood Disorders; Morphology; Mus; Neuraxis; Neurons; Neurotic Disorders; Neurotransmitters; Obsessive-Compulsive Disorder; Organism; Oxides; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Population; Potassium Channel; Predisposition; Prefrontal Cortex; Pregnancy; Prevention strategy; Process; Promoter Regions; Property; Protocols documentation; Publishing; 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; treatment strategy

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 preiviously 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 vyill 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 anatomy of the serotonin system in PNFLX treated mice. Finally, our fourth aim will investigate the causal involvement of raphe activity in the etiology of depression and anxiety-like behaviors.

5-羟色胺（5-HT）作为一种神经递质和一种生长因子来调节大脑功能