Brain Noradrenergic Neurons Peptides and Stress

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醒，可能表现为精神和/或行为病理。具体而言，本研究探讨了应激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）系统的活性，这是一个涉及情绪唤醒的神经系统。CRF被认为是一种神经调节剂，在压力下激活LC-NE系统，促进对压力的唤醒和行为反应。两个互补的过程，一个细胞和一个系统，最终决定LC-NE系统对CRF和应力的响应幅度将被检查。由于CRF受体（CRFr）的细胞定位决定了LC突触后对CRF和应激源的敏感性，AIM 1将利用电子显微镜表征LC神经元中CRFr运输的细胞内动力学。将调查CRFr运输的时间和药理学决定因素。此外，这一过程将在CRF功能障碍的遗传模型中进行检验，该模型可能模仿情感性障碍，即CRF过表达小鼠。除了刺激LC神经元的急性能力外，CRF还促进LC树突的延伸，这是一种长期的结构效应，可以决定与编码情绪信息的边缘传入事件的沟通程度。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AIM验证了crf诱导的LC树突向LC周围延伸增加了与边缘传入事件的接触以及边缘对LC- ne系统的影响，从而转化为增强的情绪唤起的假设。CRF效应的发育依赖性将被确定。此外，这种影响将在CRF功能障碍的遗传模型中进行评估。这些互补的目标整合了细胞、系统和行为方法，以理解决定LC-NE唤醒系统反应强度的机制。这些发现通过提高我们对以下方面的认识，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)压力易感性的遗传决定因素；4)压力相关病理的药理学操作。压力是易患许多使人衰弱的精神疾病的主要决定因素，包括抑郁、焦虑和药物滥用。这项研究旨在阐明压力改变活动和/或控制觉醒、注意力和情绪的脑细胞结构的机制和途径。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。

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.