COBRE:UVM PROJ 2:MOLECULAR & GENETIC ANALYSIS OF LEARNED FEAR REDUCTION IN MICE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。一次单一的创伤经历可能导致过度普遍的恐惧，就像创伤后应激障碍(PTSD)所观察到的那样。为了了解这些障碍，基础研究集中在识别负责获得巴甫洛夫条件性恐惧的神经系统。在临床上，这些障碍中的一个主要问题是无法抑制创伤记忆和相关的恐惧。因此，一个重要的研究领域涉及如何减少或抑制不想要的记忆。分子和基因技术的最新进展为研究减少恐惧的分子基础提供了前所未有的机会。实验正在研究消亡的分子和遗传基础，以及条件性恐惧消退的调节机制。通过更新和恢复程序来研究消退的调制，在这些程序中，当音调被呈现在消亡环境之外(更新)时，或者当该音调随后被呈现在厌恶的环境中时(恢复)，对音调的消除的恐惧被恢复。在特定目标1中，我们研究了C57BL/6和DBA/2小鼠的灭绝、更新和恢复。我们发现，在成功灭绝后，灭绝记忆可以保留长达6周。我们发现在DBA2/J小鼠中没有更新和恢复。我们还发现，与大鼠一样，C57小鼠的恢复也是特定于背景的。《特定目标2》的工作已经停止。在特定的目标3中，我们研究了CREB在转基因CREB可诱导阻遏基因小鼠的恢复中的作用。我们有初步证据表明，通过激活CREB抑制因子转基因来降低CREB功能会干扰恢复。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A single traumatic experience can result in the development of over generalized fear, as observed in Posttraumatic Stress Disorder (PTSD). To understand these disorders, basic research has focused on identifying the neural systems that are responsible for the acquisition of Pavlovian conditioned fear. Clinically, a major problem seen in these disorders is an inability to inhibit the traumatic memories and the associated fear. Hence, an important area of inquiry concerns the way unwanted memories can be reduced or inhibited. Recent advances in molecular and genetic techniques have provided an unprecedented opportunity to examine the molecular basis of fear reduction. Experiments are examining the molecular and genetic basis of extinction and the modulation of extinction of conditioned fear. The modulation of extinction is being examined with renewal and reinstatement procedures in which extinguished fear to a tone is recovered when the tone is presented outside of the extinction context (renewal) or when the tone is subsequently presented in an aversive context (reinstatement). In Specific Aim 1 we have examined extinction, renewal and reinstatement in C57BL/6 and DBA/2 mice. We have found that following successful extinction, extinction memory is retained for up to 6 weeks. We have found that renewal and reinstatement are absent in DBA2/J mice. We have also found that reinstatement in C57 mice is context specific as it is in rats. Work on Specific Aim 2 has been halted. In Specific Aim 3 we have examined the contribution of CREB to reinstatement in mice transgenic for an inducible repressor of CREB. We have preliminary evidence that decreasing CREB function by activating the CREB repressor transgene interferes with reinstatement.