Stress-induced CRF actions on fear and anxiety

41个残基的神经肽CRF最初的特征是它能够通过在人类体内触发皮质醇的释放来激活应激轴，在啮齿动物中引发皮质酮的释放，已经被证明介导了应激的许多效应。CRF通过两种G蛋白依赖受体亚型CRF1和CRF2发挥作用，这两种受体分别参与调节恐惧和焦虑的形成。通过激活海马区CRF1和激活外侧中间隔区的CRF2，作为条件性恐惧的恐惧条件化的学习被增强。焦虑样行为通过激活CRF1或隔部CRF2而增加，CRF2或CRF1激活或阻断CRF1-两者均可通过脑室访问-可减少焦虑样行为。CRF1和CRF2都参与了对应激性刺激的反应。我们在初步实验中观察到，暴露于作为应激刺激的固定状态下的小鼠，随后在增加停顿后进行恐惧条件反射训练，出现了初始记忆缺陷，并在应激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，防止了记忆缺陷。我们假设，类似焦虑的行为和记忆是负相关的。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，并借助体外实验定位各种受体亚群。我们将应用恐惧条件反射，高架迷宫测试，老鼠防御测试电池和大鼠 暴露试验作为野生型小鼠和CRF1基因缺陷小鼠结构性或条件性缺失的行为范式。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有关，并且只有选定的压力诱导的焦虑形式才能调节记忆形成过程，正如恐惧条件反射结果所表明的那样。产生焦虑的细胞生物学和解剖学细节很可能比焦虑症状的严重程度对记忆形成的影响更重要。在这些考虑的基础上，这项建议对精神障碍，如创伤后应激障碍和精神障碍，其中压力调节认知过程具有重要意义。

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.