The dorsal raphe and CRF: making the connections

中缝背侧和 CRF：建立联系

• 批准号: 7143656
• 负责人: MICHAEL S CLARK
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143656
• 关键词: Adenoviridae; amygdala; animal genetic material tag; anxiety; behavioral /social science research tag; cell line; corticotropin releasing factor; depression; dorsal raphe nucleus; gene targeting; genetically modified animals; hormone receptor; laboratory mouse; laboratory rat; neural information processing; neuroanatomy; neuronal transport; neuropeptides; neuroregulation; prosencephalon; second messengers; serotonin; stress; transfection

DESCRIPTION (provided by applicant): Depression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States, and are highly associated with exposure to stress. Impaired serotonin neurotransmission appears to be a central mechanism inducing depressive and anxiety symptoms. Previous studies have suggested that corticotropin releasing factor (CRF) receptor activation in the dorsal raphe, a major source of serotonin to the forebrain, is a critical mechanism underlying stress effects on serotonergic systems. However, the effects of CRF on dorsal raphe vary depending on dose, location within the nucleus, and receptor specificity. The origin of CRF projections to the dorsal raphe, and their potential to be regulated by dorsal raphe outputs is also unknown. Nor are the roles in stress response of the several neuropeptides increasingly recognized as co-transmitters with serotonin that may be involved in the effects of chronic stress. I will use a serotonergic cell line, RN46A-B14 to model the dose response and second messenger effects of CRF receptor activation on serotonergic neurons, helping to elucidate the direct effects of CRF there. Using a novel retrograde gene transfer system, canine adenovirus-2, 1 will determine the origins of CRF projection to the various subregions of the dorsal raphe, suspected to be the central nucleus of the amygdala and bed nucleus stria terminalis. I will also determine reciprocal projections of the dorsal raphe to these regions, delineating the circuitry that could underlie intrinsic neuromodulation, a phenomena that may underlie some of the long lasting behavioral alterations associated with stress. Finally, I will also produce a conditional knockout Tph2 transgenic mouse and determine the ability of a canine adenovirus-Cre recombinase vector to specifically alter serotonergic transmission in defined pathways. This methodology will allow me to separate the role of serotonin from the role of peptide co-transmitters in behavior. These studies will help develop technologies to understand the role of CRF projections to the dorsal raphe, and the role of dorsal raphe outputs in modulating circuits that underlie behavior related to anxiety and depression. The public health importance of this basic research is substantial. Understanding the mechanisms by which stress is communicated opens opportunities for intervening in this process. Given the role of stress in the development and recurrence of many psychiatric disorders, the ability to disrupt the communication of stress context would be a boon for both the treatment and prevention of many types of mental illness, including depression and anxiety disorders. This research will help provide the information necessary for the rational development of such interventions.

描述（由申请人提供）：抑郁症和焦虑症是美国发病、死亡和残疾的主要原因之一，并且与压力密切相关。血清素神经传递受损似乎是诱发抑郁和焦虑症状的核心机制。先前的研究表明，中缝背侧促肾上腺皮质激素释放因子（CRF）受体的激活是前脑血清素的主要来源，是压力对血清素能系统产生影响的关键机制。然而，CRF 对中缝背侧的影响因剂量、核内位置和受体特异性而异。 CRF 投射到中缝背侧的起源以及它们受中缝背侧输出调节的潜力也是未知的。几种神经肽在应激反应中的作用也越来越多地被认为是可能与慢性应激的影响有关的血清素的共同递质。我将使用血清素能细胞系 RN46A-B14 来模拟 CRF 受体激活对血清素能神经元的剂量反应和第二信使效应，帮助阐明 CRF 在那里的直接影响。使用新型逆行基因转移系统，犬腺病毒-2, 1将确定CRF投射到中缝背侧各个亚区域的起源，怀疑是杏仁核和终纹床核的中央核。我还将确定中缝背侧到这些区域的相互投影，描绘出可能构成内在神经调节的电路，这种现象可能是与压力相关的一些长期行为改变的基础。最后，我还将制备条件性敲除 Tph2 转基因小鼠，并确定犬腺病毒-Cre 重组酶载体特异性改变特定途径中血清素能传递的能力。这种方法将使我能够将行为中血清素的作用与肽协同递质的作用分开。这些研究将有助于开发技术来了解 CRF 投射对中缝背侧的作用，以及中缝背侧输出在调节与焦虑和抑郁相关的行为背后的回路中的作用。这项基础研究对公共卫生的重要性是巨大的。了解压力传递的机制为干预这一过程提供了机会。鉴于压力在许多精神疾病的发生和复发中的作用，破坏压力环境沟通的能力将有利于治疗和预防许多类型的精神疾病，包括抑郁症和焦虑症。这项研究将有助于为此类干预措施的合理发展提供必要的信息。