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Stress psychopathology and the amygdala

压力精神病理学和杏仁核

基本信息

批准号：
7456272
负责人：
Norman BRADLEY KEELE
金额：
$ 19.88万
依托单位：
BAYLOR UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456272
关键词：
Action Potentials Adult Affective Aggressive behavior Amygdaloid structure Animal Model Anticonvulsants Anxiety Anxiety Disorders Area Award Behavior Behavioral Biological Brain Cell Nucleus Chemosensitization Chronic Cues Data Emotional Emotional disorder Emotions Epilepsy Excision Fenclonine Fire - disasters Fright Glutamates Goals Grant Housing In Vitro Institution Lateral Learning Ligands Limbic System Link Measures Mediating Membrane Mental disorders Mood Disorders Moods Neurons Neurotransmitters Output Patients Personal Satisfaction Phenotype Phenytoin Physiological Physiology Population Process Property Psychopathology Public Health Purpose Rattus Research Research Personnel Resources Role Saline Sampling Science Seizures Sensory Serotonin Slice Stimulus Stress Structure Students Symptoms System Temporal Lobe Epilepsy Testing Translating Tryptophan 5-monooxygenase Universities Whole-Cell Recordings base behavioral pharmacology career conditioned fear experience in vivo inhibitor/antagonist innovation neurobiological mechanism neuronal excitability neurophysiology postsynaptic receptor relating to nervous system response serotonin receptor transmission process

项目摘要

DESCRIPTION (provided by applicant): As the neurobiological mechanisms underlying emotional-affective disorders anxiety are emerging, critical roles are suggested for the amygdala and the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT). However, the amygdala is also a common focus of excessive neuronal activity that manifests as temporal lobe epilepsy, and these patients may experience disturbed mood or anxiety. This suggests a link between emotion and epilepsy, and more specifically that excitability in the amygdala is important in controlling emotion. In evidence, some anticonvulsants also have mood-stabilizing properties. Mood and anxiety disorders may also involve low 5-HT levels since compounds acting on the 5-HT system are first-line treatments for many emotional disorders. Still, little is known about the cellular mechanisms of 5-HT in the amygdala. The purpose of this project is to examine the effects of low 5-HT in the amygdala on mechanisms controlling neuronal excitability in this important limbic area. The overall hypothesis is that low 5-HT in the amygdala leads to increased neuronal excitability that underlies pathological emotional behavior. Specifically, this project will determine if low 5-HT in the amygdala results in changes in fear behavior in vivo, and increases neuronal excitability in neurons of the lateral amygdala (LA) nucleus in vitro. We will determine the mechanism of action of low 5-HT-mediated changes in excitability of LA neurons and how this is involved in abnormal fear behavior. Preliminary studies show that 5-HT2 receptors are involved in the behavioral changes induced by low 5-HT, and that 5-HT2 receptors inhibit the hyperpolarization-activated current, IH, which regulates neuronal excitability. The specific aims of this application are to: (1) analyze the behavioral pharmacology of low-5-HT-induced changes in cued and contextual fear- conditioning in rats by intra-amygdala administration of 5-HT2 receptor ligands and the IH blocker ZD-7288; (2) define the physiological and pharmacological mechanisms involved in the 5-HT receptor control of IH using whole-cell recordings in brain slices containing the lateral nucleus of the amygdala. We will use an innovative and integrative approach that combines in vivo behavioral studies with in vitro physiology of amygdala neurons to gain important new information about the 5-HT-mediated mechanisms of excitability in the amygdala and the functional role of 5-HT2 receptors in fear behavior. By analyzing the cellular mechanisms of 5-HT in the amygdala and their functional role in fear behavior, this project may identify new targets involved in mood and anxiety disorders. This project will be accomplished at Baylor University, a primarily undergraduate institution where scientific research is an established priority. Award of this AREA grant will provide important resources necessary to help gifted students conduct original research as they prepare for careers in biomedical science. PUBLIC HEALTH RELEVANCE: Mood and anxiety disorders are a major public health concern since approximately 18% of the adult US population has an anxiety disorder, and 10% have a mood disorder. By understanding the biological substrates of fear and anxiety in an animal model of emotional behavior, this project may make a significant contribution to the well-being of people with mental illness by revealing new targets that contribute to symptoms of mood and anxiety disorders.

描述（由申请人提供）：随着情绪-情感障碍焦虑的神经生物学机制的出现，杏仁核和神经递质5-羟色胺（5-羟色胺或5-HT）的关键作用被提出。然而，杏仁核也是过度神经元活动的共同焦点，表现为颞叶癫痫，这些患者可能会出现情绪紊乱或焦虑。这表明情绪和癫痫之间存在联系，更具体地说，杏仁核的兴奋性在控制情绪方面很重要。有证据表明，一些抗惊厥药也具有稳定情绪的特性。情绪和焦虑障碍也可能涉及低5-羟色胺水平，因为作用于5-羟色胺系统的化合物是许多情绪障碍的一线治疗方法。然而，我们对杏仁核中5-羟色胺的细胞机制知之甚少。本项目的目的是研究杏仁核低5-羟色胺对控制这一重要边缘区域神经元兴奋性的机制的影响。总的假设是，杏仁核中5-羟色胺含量低导致神经元兴奋性增加，这是病理性情绪行为的基础。具体来说，本项目将确定体内杏仁核中5-羟色胺含量低是否会导致恐惧行为的改变，并在体外增加外侧杏仁核（LA）神经元的神经元兴奋性。我们将确定低5- ht介导的LA神经元兴奋性变化的作用机制及其与异常恐惧行为的关系。初步研究表明，5-HT2受体参与低5-HT诱导的行为改变，5-HT2受体抑制调节神经元兴奋性的超极化激活电流IH。本应用的具体目的是：(1)通过在杏仁核内给药5-HT2受体配体和IH阻滞剂ZD-7288，分析低5-HT2诱导的大鼠线索和情境恐惧条件反射变化的行为药理学；(2)利用含有杏仁核外侧核的大脑切片的全细胞记录，确定5-HT受体控制IH的生理和药理学机制。我们将采用一种创新和综合的方法，将体内行为研究与杏仁核神经元的体外生理学相结合，以获得关于5-HT2介导的杏仁核兴奋性机制和5-HT2受体在恐惧行为中的功能作用的重要新信息。通过分析杏仁核中5-羟色胺的细胞机制及其在恐惧行为中的功能作用，本项目可能会发现与情绪和焦虑障碍有关的新靶点。该项目将在贝勒大学完成，这是一个主要的本科生机构，科学研究是一个确定的优先事项。这一领域的拨款将提供必要的重要资源，帮助天才学生进行原创性研究，为他们在生物医学科学领域的职业生涯做准备。公共卫生相关性：情绪和焦虑障碍是一个主要的公共卫生问题，因为大约18%的美国成年人患有焦虑症，10%的人患有情绪障碍。通过了解动物情绪行为模型中恐惧和焦虑的生物学基础，该项目可能会通过揭示导致情绪和焦虑障碍症状的新靶点，为精神疾病患者的福祉做出重大贡献。