Brain Noradrenergic Neurons Peptides and Stress

大脑去甲肾上腺素能神经元肽和压力

• 批准号: 7862318
• 负责人: RITA VALENTINO
• 金额: $ 36.29万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862318
• 关键词: Acute; Adrenal Glands; Adult; Agonist; Anxiety; Arousal; Attention; Behavioral; Brain; Chronic stress; Clinical; Cognitive; Communication; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Degradation Pathway; Dendrites; Dependence; Detection; Development; Disease; Dose; Electron Microscopy; Emotional; Emotions; Exposure to; Functional disorder; Genetic; Genetic Determinism; Genetic Models; Growth; Hypotension; Hypothalamic structure; In Vitro; Knock-out; Knowledge; Laboratories; Life Stress; Ligand Binding; Limb structure; Mediating; Medical; Mental Depression; Mental Health; Mental disorders; Mood Disorders; Morphology; Mus; Neonatal; Neurobehavioral Manifestations; Neuromodulator; Neurons; Neuropeptides; Norepinephrine; Organelles; Pathology; Pathway interactions; Peptides; Physiological; Pituitary Gland; Play; Post-Traumatic Stress Disorders; Process; Progress Reports; Psyche structure; Recording of previous events; Regulation; Research; Role; Slice; Stress; Structure; Substance abuse problem; Swimming; Symptoms; System; Testing; Translating; Work; biological adaptation to stress; brain cell; clinically relevant; depressive symptoms; design; hypothalamic-pituitary-adrenal axis; in vivo; locus ceruleus structure; mouse model; noradrenergic; norepinephrine system; overexpression; postsynaptic; prevent; public health relevance; receptor; receptor internalization; relating to nervous system; research study; response; social stress; stress related disorder; stressor; trafficking

DESCRIPTION (provided by applicant): The long-term objective of this research is to elucidate mechanisms by which stress causes enduring changes in neural systems that mediate emotional arousal that may be expressed as mental and/or behavioral pathology. Specifically, this research examines how the stress neuromediator, corticotropin-releasing factor (CRF) regulates activity of the locus coeruleus (LC)-norepinephrine (NE) system, a neural system involved in emotional arousal. CRF has been implicated as a neuromodulator that activates the LC-NE system during stress, an effect that facilitates arousal and behavioral responses to stress. Two complementary processes, one cellular and one systems, that ultimately determine the magnitude of response of the LC-NE system to CRF and stress will be examined. Because the cellular localization of the CRF receptor (CRFr) determines LC postsynaptic sensitivity to CRF and to stressors, AIM 1 will characterize the intracellular dynamics of CRFr trafficking in LC neurons using electron microscopy. Temporal and pharmacological determinants of CRFr trafficking will be investigated. Additionally, this process will be examined in a genetic model of CRF dysfunction that may mimic affective disorders, i.e., the CRF overexpressing mouse. In addition to its acute ability to excite LC neurons, CRF promotes extension of LC dendrites, a long-term structural effect that can determine the degree of communication with limbic afferents encoding emotional information. AIM 2 will identify conditions in which this structural effect occurs in vivo and its functional consequences. This AIM tests the hypothesis that CRF-induced LC dendritic extension into the peri-LC increases contacts with limbic afferents and the limbic influence over the LC-NE system, thereby translating to enhanced emotional arousal. The developmental dependence of this effect of CRF will be determined. Additionally this effect will be assessed in genetic models of CRF dysfunction. These complementary AIMs integrate cellular, systems and behavioral approaches towards understanding mechanisms that determine the magnitude of response of the LC-NE arousal system. The findings have direct clinical implications by advancing our knowledge of 1) the impact of early life stress on mental health, 2) the impact of social stress on mental health, 3) genetic determinants of stress vulnerability and 4) pharmacologic manipulation of stress-related pathology. PUBLIC HEALTH RELEVANCE Stress is a major determinant of vulnerability to many debilitating psychiatric disorders, including depression, anxiety and substance abuse. This research is designed to elucidate the mechanisms and pathways by which stress alters activity and/or the structure of brain cells that control arousal, attention and emotion. This knowledge will advance our ability to prevent and/or alleviate these debilitating stress-related disorders.

描述（由申请人提供）：本研究的长期目标是阐明压力导致神经系统持久变化的机制，这些变化介导情绪唤起，可能表现为精神和/或行为病理学。具体来说，这项研究探讨了压力神经介质促肾上腺皮质激素释放因子 (CRF) 如何调节蓝斑 (LC)-去甲肾上腺素 (NE) 系统（一种参与情绪唤醒的神经系统）的活动。 CRF 被认为是一种神经调节剂，可在压力期间激活 LC-NE 系统，从而促进对压力的唤醒和行为反应。将检查两个互补过程，一个细胞过程和一个系统过程，最终决定 LC-NE 系统对 CRF 和应激的反应程度。由于 CRF 受体 (CRFr) 的细胞定位决定了 LC 对 CRF 和应激源的突触后敏感性，因此 AIM 1 将使用电子显微镜表征 LC 神经元中 CRFr 运输的细胞内动态。将研究 CRFr 贩运的时间和药理学决定因素。此外，还将在可能模拟情感障碍的 CRF 功能障碍遗传模型（即 CRF 过度表达小鼠）中检查这一过程。除了具有激发 LC 神经元的敏锐能力外，CRF 还能促进 LC 树突的延伸，这是一种长期结构效应，可以决定与编码情感信息的边缘传入神经的沟通程度。 AIM 2 将确定这种结构效应在体内发生的条件及其功能后果。该目的测试了以下假设：CRF 诱导的 LC 树突向 LC 周围的延伸增加了与边缘传入神经的接触以及边缘对 LC-NE 系统的影响，从而转化为增强的情绪唤醒。 CRF 的这种效应的发育依赖性将被确定。此外，这种效应将在 CRF 功能障碍的遗传模型中进行评估。这些互补的 AIM 整合了细胞、系统和行为方法，以了解决定 LC-NE 唤醒系统反应幅度的机制。这些发现通过提高我们对以下方面的认识而具有直接的临床意义：1）早期生活压力对心理健康的影响；2）社会压力对心理健康的影响；3）压力脆弱性的遗传决定因素；4）压力相关病理学的药理操作。公共卫生相关性 压力是导致许多使人衰弱的精神疾病（包括抑郁、焦虑和药物滥用）脆弱性的主要决定因素。这项研究旨在阐明压力改变控制唤醒、注意力和情绪的脑细胞活动和/或结构的机制和途径。这些知识将提高我们预防和/或减轻这些使人衰弱的压力相关疾病的能力。