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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。单一的创伤经历可能导致过度普遍恐惧的发展，正如创伤后应激障碍（PTSD）所观察到的那样。为了理解这些障碍，基础研究集中在识别负责获得巴甫洛夫条件恐惧的神经系统。在临床上，这些疾病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必要的记忆。分子和遗传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。实验正在研究灭绝的分子和遗传基础以及条件恐惧灭绝的调制。灭绝的调制正在审查与更新和恢复程序，其中消失的恐惧，以一个音调恢复时，音调是在灭绝的背景（更新）之外，或当音调随后在一个令人厌恶的背景（恢复）。在具体目标1中，我们检查了C57 BL/6和DBA/2小鼠的消退、更新和恢复。我们发现，在成功灭绝之后，灭绝记忆可以保留长达6周。我们已经发现在DBA 2/J小鼠中不存在更新和恢复。我们还发现，在C57小鼠中的恢复与在大鼠中一样具有背景特异性。具体目标2的工作已经停止。在具体目标3中，我们研究了CREB对CREB诱导型阻遏物转基因小鼠恢复的贡献。我们有初步的证据表明，通过激活CREB阻遏基因降低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.