Stress-induced CRF actions on fear and anxiety

压力诱导的 CRF 对恐惧和焦虑的作用

• 批准号: 6964557
• 负责人: Joachim Spiess
• 金额: $ 24.74万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964557
• 关键词: anxiety; autoradiography; biological models; clinical research; conditioning; cooperative study; corticotropin releasing factor; fear; hormone metabolism; hormone regulation /control mechanism; interdisciplinary collaboration; laboratory mouse; minority institution research support; model design /development; neurobiology; neuroendocrine system; neurosciences; psychological defense mechanism; stress

The 41-residue neuropeptide CRF originally characterized on the basis of its ability to activate the stress axis by triggering the release of cortisol in humans and corticosterone in rodents, has been demonstrated to mediate many effects of stress. CRF exhibits its actions through two G protein-dependent receptor subtypes, CRF1 and CRF2, which are differentially involved in the modulation of fear and anxiety formation. Learning measured by fear conditioning as conditioned fear is enhanced by activation of hippocampal CRF1 and impaired by activation of CRF2 of the lateral intermediate septum. Anxiety-like behavior is increased by activation of CRF1 - accessible through the brain ventricle system - or septal CRF2 and is reduced by activation of CRF2 or blockade of CRF1 -both accessible through the brain ventricles. Both CRF1 and CRF2 are involved in the response to a stressful stimulus. We observed in preliminary experiments that mice exposed to immobilization serving as stressful stimulus and subsequently, after increasing pauses, trained for fear conditioning, suffered from an intitial memory deficit from which they recovered within one hour after :he end of the stressful exposure. Interestingly, activation of a subpopulation of CRF2 lowered the anxiety-like behavior and prevented the memory deficit. We hypothesize that anxiety-like behavior and memory are inversely related. To obtain more insight into these behaviors, we now want to extend our analysis to defensive behaviors and locate the various receptor subpopulations with the help of ex vivo experiments. We will apply fear conditioning, the Elevated Plus Maze test, the Mouse Defense Test Battery and the Rat Exposure Test as behavioral paradigms to wild type mice and CRF1-deficient mice constitutively or conditionally lacking the CRF1 gene. We expect that this study will provide evidence that in the mouse model stress is linked to defined anxiety forms and that only selected stress-induced anxiety forms modulate the memory formation process as indicated by the fear conditioning results. It may well be that the cell biological and anatomical details of generating anxiety are more important for the impact on memory formation than the severity of the anxiety symptoms. On the basis of these considerations, this proposal is significant for psychiatric disorders such as PTSD and psychotic disorders in which stress modulates cognitive processes.

41 个残基的神经肽 CRF 最初的特征是其通过触发人类皮质醇和啮齿动物皮质酮的释放来激活应激轴的能力，已被证明可以介导压力的许多影响。 CRF 通过两种 G 蛋白依赖性受体亚型 CRF1 和 CRF2 发挥作用，这两种亚型分别参与恐惧和焦虑形成的调节。通过恐惧调节来测量学习能力，因为条件性恐惧通过海马 CRF1 的激活而增强，并通过外侧中间隔膜的 CRF2 的激活而减弱。激活CRF1（可通过脑室系统进入）或间隔CRF2可增加焦虑样行为，而通过激活CRF2或阻断CRF1（均可通过脑室进入）可减少焦虑样行为。 CRF1 和 CRF2 都参与对压力刺激的反应。我们在初步实验中观察到，小鼠受到固定作为压力刺激，随后，在增加停顿后，进行恐惧调节训练，小鼠出现初始记忆缺陷，并在压力暴露结束后一小时内恢复。有趣的是，CRF2 亚群的激活降低了焦虑样行为并防止了记忆缺陷。我们假设焦虑样行为和记忆呈负相关。为了更深入地了解这些行为，我们现在希望将我们的分析扩展到防御行为，并借助离体实验来定位各种受体亚群。我们将应用恐惧调节、高架迷宫测试、小鼠防御测试电池和大鼠 暴露测试作为野生型小鼠和结构性或条件性缺乏 CRF1 基因的 CRF1 缺陷小鼠的行为范例。我们期望这项研究将提供证据，证明在小鼠模型中，压力与特定的焦虑形式相关，并且只有选定的压力诱发的焦虑形式才能调节记忆形成过程，如恐惧条件反射结果所示。很可能产生焦虑的细胞生物学和解剖学细节对记忆形成的影响比焦虑症状的严重程度更重要。基于这些考虑，该提议对于精神疾病（例如创伤后应激障碍（PTSD）和压力调节认知过程的精神障碍）具有重要意义。