Effect of Stress on Glutamate Receptors and Signaling Proteins in the Basolateral

压力对基底外侧谷氨酸受体和信号蛋白的影响

• 批准号: 7684948
• 负责人: Emil CHRIS MULY
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684948
• 关键词: AMPA Receptors; Affect; Alcohol abuse; Amygdaloid structure; Animal Behavior; Animals; Anxiety; Anxiety Disorders; Architecture; Award; Behavior; Behavioral; Biochemical; Brain; Brain region; Clinical; Commit; Communication; Complex; Control Animal; Data; Dendritic Spines; Dependence; Development; Disease; Drug abuse; Electrons; Environment; Excitatory Synapse; Exposure to; Funding; Gene Expression; Gene Proteins; Glutamate Receptor; Glutamates; Goals; Health; Healthcare; Human; Image; Immobilization; Immunoelectron Microscopy; Immunoperoxidase Technics; In Vitro; Label; Lead; Mediating; Medical; Mental Depression; Methods; Microscopic; Military Personnel; Mission; Modeling; Molecular; Molecular Target; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Nervous System Physiology; Neurons; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Post-Traumatic Stress Disorders; Process; Proteins; Rattus; Receptor Signaling; Relapse; Relative (related person); Research; Resolution; Resources; Rodent Model; Role; Schizophrenia; Signal Transduction; Signaling Protein; Site; Slice; Stimulus; Stress; Substance abuse problem; Symptoms; Synapses; Synaptic plasticity; System; Testing; Time; Vertebral column; Veterans; calmodulin-dependent protein kinase II; conditioned fear; density; design; exposed human population; interest; neurotransmission; novel; patient population; postsynaptic; protein distribution; public health relevance; response; stress related disorder; stressor

DESCRIPTION (provided by applicant): Stress is a powerful stimulus that modulates animal behavior and the functioning of the nervous system. In people, stress negatively impacts a variety of psychiatric conditions relevant to the clinical mission of the Department of Veterans Affairs, including depression, anxiety and substance abuse. In particular, exposure to severe stress is associated with posttraumatic stress disorder (PTSD), both in military and civilian populations. These conditions are a major health issue for our veteran population and available treatments are at best partially effective. There is a pressing need to better understand the effect of stress on the functioning of the brain in order to design better treatments for stress related disorders. Studies in humans and animals have indicated that the amygdala is a brain region involved in mediating the behavioral responses to stress, and patients' with PTSD show elevated activity in this brain region. In particular the basolateral complex of the amygdala (BLA) is critical to normal and pathological amygdala functioning. The BLA's response to stress has been shown to involve synaptic plasticity of the excitatory, glutamatergic connections within this brain region. While complex synaptic plasticity is a complex phenomenon, many studies have indicated that it involves the NMDA and AMPA subtypes of glutamate receptor, as well as the signal transduction protein CaMKII. Manipulations that block the activity of these proteins block behavioral responses to stress. There is evidence that the response of these proteins to altered activity levels and stress involves altered patterns of localization. It is the goal of this proposal to study this issue in more detail using immunohistochemical localization of the NR1 and GluR1 subunits of the NMDA and AMPA receptors and CaMKII and high resolution electron microscopic examination. We will use a rodent model of repeated, severe stress- repeated immobilization stress to study the effect of stress in the BLA. We will begin by determining the time course of how stress alters the localization of these proteins in the BLA. We will next use an in vitro system to assess how these proteins are affected by altered activity patterns in the BLA and how prior stress exposure modifies the amygdala's response to activity. Finally, we will use post-embedding immunogold labeling to study how stress affects the composition of the postsynaptic density in the BLA. These studies will provide a detailed understanding of the molecular architecture of excitatory neurotransmission in the BLA and determine how this is altered by prior stress exposure. This information will enhance our understanding of stress affects in this critical brain region and suggest possible molecular targets for novel therapies for stress related disorders, including PTSD. PUBLIC HEALTH RELEVANCE: Stress plays a significant role in modifying behavior and may lead to, or worsen, a variety of psychiatric conditions relevant to the clinical mission of the Department of Veterans Affairs. Stress can precipitate or worsen episodes of depression and a variety of different anxiety disorders. Stress is associated with worsening symptoms in schizophrenia. Stress is associated with relapse in alcohol and drug abuse and dependence. In particular, we now recognize that severe stressors can be associated with the development of post-traumatic stress disorder (PTSD) in both civilian and military populations. These conditions afflict large numbers of our veteran population. Substantial resources have been committed to the care of these patients, and further, these disorders can increase a patient's use of healthcare resources for other medical problems. While importance of stress and stress related illnesses is clearly established, our treatments remain partially effective at best. Here we propose research to better understand the effect of stress in a critical brain region, the amygdala. The amygdala is a brain region involved in PTSD and the brain's response to stress. Stress has been shown to alter the circuitry and functioning of the amygdala. In this proposal we will investigate how the organization of key molecules, involved in excitatory communication in the amgygdala, is altered by stress. The results of the proposed studies will further our understanding of stress induced changes in the amygdala and suggest specific molecular targets for new drug treatments for stress related disorders, including PTSD.

描述（由申请人提供）： 压力是一种强大的刺激，可调节动物行为和神经系统的功能。在人们中，压力对与退伍军人事务部的临床任务有关的各种精神病疾病产生负面影响，包括抑郁，焦虑和滥用药物。特别是，在军事和平民种群中，暴露于严重的压力与创伤后应激障碍（PTSD）有关。对于我们的资深人口来说，这些情况是一个主要的健康问题，可用的治疗最多有效。迫切需要更好地理解压力对大脑功能的影响，以设计更好的压力相关疾病治疗方法。人类和动物的研究表明，杏仁核是介导对压力的行为反应的大脑区域，而患有PTSD的患者在该大脑区域的活性升高。特别是杏仁核（BLA）的基底外侧复合物对于正常和病理杏仁核的功能至关重要。 BLA对应激的反应已显示出该大脑区域内兴奋性谷氨酸能连接的突触可塑性。尽管复杂的突触可塑性是一种复杂的现象，但许多研究表明，它涉及谷氨酸受体的NMDA和AMPA亚型，以及信号转导蛋白CAMKII。阻断这些蛋白质活性的操纵阻断了对压力的行为反应。有证据表明，这些蛋白质对改变活性水平和压力的反应涉及改变定位模式。该提案的目标是使用NMDA和AMPA受体的NR1和GLUR1亚基以及CAMKII以及CAMKII以及高分辨率电子显微镜检查更详细地研究此问题。我们将使用重复的，严重的重复固定应力的啮齿动物模型来研究BLA应力的影响。我们将首先确定压力如何改变这些蛋白质在BLA中的定位的时间过程。接下来，我们将使用体外系统来评估这些蛋白质如何受到BLA活性模式的影响，以及先前的压力暴露如何改变杏仁核对活动的反应。最后，我们将使用后装置的免疫金标记来研究应力如何影响BLA中突触后密度的组成。 这些研究将对BLA中兴奋性神经传递的分子结构提供详细的理解，并确定如何通过先前的压力暴露来改变这种情况。这些信息将增强我们对这个关键大脑区域压力影响的理解，并提出可能针对应激相关疾病（包括PTSD）的新型疗法的分子靶标。 公共卫生相关性： 压力在修改行为中起着重要作用，可能导致或恶化与退伍军人事务部临床使命相关的各种精神病疾病。 压力会导致抑郁症和多种不同焦虑症的发作。 压力与精神分裂症的症状恶化有关。 压力与酒精，药物滥用和依赖性的复发有关。 特别是，我们现在认识到，在平民和军事人群中，严重的压力源可能与创伤后应激障碍（PTSD）的发展有关。 这些条件困扰着我们的资深人数。 大量资源已致力于照顾这些患者，此外，这些疾病可以增加患者将医疗保健资源用于其他医疗问题的使用。 尽管明确确定了压力和压力与压力相关疾病的重要性，但我们的治疗方法充其量仍然有效。 在这里，我们提出研究，以更好地理解关键大脑区域杏仁核的影响。 杏仁核是参与PTSD的大脑区域以及大脑对压力的反应。 已证明应力改变了杏仁核的电路和功能。 在该提案中，我们将调查如何通过压力改变参与AMGYGDALA兴奋性交流的关键分子的组织。 拟议的研究的结果将进一步理解压力引起的杏仁核变化，并提出针对应激相关疾病（包括PTSD）的新药物治疗的特定分子靶标。