Stress-induced CRF actions on fear and anxiety

41残基神经肽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，已被证明可以介导许多应激效应。CRF通过两种G蛋白依赖受体亚型CRF1和CRF2发挥作用，这两种受体亚型在恐惧和焦虑形成的调节中起着不同的作用。作为条件性恐惧的恐惧条件反射测量的学习通过激活海马CRF1而增强，并通过激活外侧中间隔CRF2而受损。焦虑样行为通过激活CRF1（可通过脑室系统）或室间隔CRF2而增加，通过激活或阻断CRF2（均可通过脑室）而减少。CRF1和CRF2都参与对应激刺激的反应。我们在初步实验中观察到，小鼠暴露在作为压力刺激的固定环境中，随后，在不断增加的停顿之后，进行恐惧条件反射训练，出现了最初的记忆缺陷，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，并在离体实验的帮助下定位各种受体亚群。我们将使用恐惧条件反射，高架迷宫测试，小鼠防御测试电池和大鼠

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.