Stress psychopathology and the amygdala

描述（由申请人提供）：随着情绪情感障碍焦虑症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）被认为起着关键作用。然而，杏仁核也是表现为颞叶癫痫的过度神经元活动的常见焦点，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，一些抗惊厥药也有稳定情绪的作用。情绪和焦虑障碍也可能涉及低5-HT水平，因为作用于5-HT系统的化合物是许多情绪障碍的一线治疗。然而，对杏仁核中5-HT的细胞机制知之甚少。本项目的目的是研究杏仁核中5-HT含量低对这一重要边缘区神经元兴奋性控制机制的影响。总的假设是，杏仁核中5-HT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，该项目将确定杏仁核中的低5-HT是否会导致体内恐惧行为的变化，并增加体外杏仁外侧核（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，以及这是如何参与异常恐惧行为的。初步研究表明，5-HT 2受体参与了低5-HT引起的行为变化，并且5-HT 2受体抑制调节神经元兴奋性的超极化激活电流IH。本申请的具体目的是：（1）通过杏仁核内给予5-HT 2受体配体和IH阻断剂ZD-7288，分析低5-HT诱导的大鼠线索和背景恐惧条件化变化的行为药理学;（2）利用全脑缺血模型，阐明5-HT受体调控IH的生理和药理学机制。包含杏仁核外侧核的脑切片细胞记录。我们将采用一种创新的综合方法，将杏仁核神经元的体内行为研究与体外生理学相结合，以获得有关杏仁核中5-HT介导的兴奋性机制和5-HT 2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-HT的细胞机制及其在恐惧行为中的功能作用，该项目可能会发现涉及情绪和焦虑障碍的新靶点。这个项目将在贝勒大学完成，贝勒大学是一个主要的本科院校，科学研究是一个既定的优先事项。该地区补助金的奖励将提供必要的重要资源，以帮助资优学生进行原创性研究，因为他们准备在生物医学科学的职业生涯。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障碍，10%的人患有情绪障碍。通过了解情绪行为动物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症症状的新目标，为精神疾病患者的福祉做出重大贡献。

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.