Cortical circuitry and mechanisms underlying remote cue-specific fear memory and extinction

项目摘要 患有创伤后应激障碍(PTSD)等恐惧障碍的个人经历 过度强烈和侵入性的恐惧记忆，关于在之前的 创伤，包括个别声音或视觉刺激(“特定线索”的恐惧记忆)或 共同定义事件发生地点的刺激组合(“背景”恐惧 内存)。这些记忆可能是最近或很久以前形成的(“远程”记忆)，在 在这种情况下，他们可能会在一个人的一生中困扰他/她的大部分时间。的发展。 有效的治疗依赖于对神经机制的透彻理解。 这些不同类型的恐惧记忆，以及恐惧消退，这是暴露的基础- 通常用于减少人类恐惧的基础疗法。到目前为止，有大量的研究 已经确定了支持最近和远程背景记忆的离散神经系统，以及 其他研究已经确定了最近获得的线索特定记忆的底物，并 灭绝，但很少有研究集中在远程提示的大脑机制上- 特定的记忆和灭绝。解决这一问题很重要，尤其是在创伤后应激障碍方面 由于个人通常在创伤事件发生后很久才寻求治疗，特别是在 战斗创伤或性侵犯。为了解决这个问题，这项拟议的研究提出了一项新的 支持远距离线索特定恐惧记忆的神经回路的理论模型 灭绝。该模型基于我们实验室的最新数据，并结合了最先进的技术 化学发生学和视神经解剖学方法检验假设a) 在脾后皮质和次级感觉皮质之间的通信是必要的 远距离线索特定的恐惧记忆，以及b)视后皮质调节情境依赖 特定于远程提示的恐惧的消亡。

Project Summary Individuals with fear disorders such as post-traumatic stress disorder (PTSD) experience excessively strong and intrusive fear memories about stimuli that were encountered during a prior trauma, including individual sounds or visual stimuli (“cue-specific” fear memory) or the combination of stimuli that together define the place in which the event occurred (“contextual” fear memory). The memories may have been formed recently or long ago (“remote” memories), in which case they may plague a person for a substantial portion of his/her life. The development of effective therapies depends on a thorough understanding the neural mechanisms that underlie these different types of fear memories, as well as fear extinction, which is the basis for exposure- based therapy commonly used to reduce fear in humans. To date, a substantial body of research has identified discrete neural systems that support recent versus remote contextual memory, and other studies have identified the substrates of recently-acquired cue-specific memory and extinction, but very little work has focused on the brain mechanisms involved in remote cue- specific memory and extinction. This is important to resolve particularly with respect to PTSD since individuals often do not seek therapy until long after the traumatic event, especially in cases of combat trauma or sexual assault. To address this, the proposed research advances a new theoretical model of the neural circuits that underlie remote cue-specific fear memory and extinction. This model is based on new data from our laboratory and combines state-of-the art chemogenetic and optogentic-anatomical approaches to test the hypotheses that a) communication between the retrosplenial cortex and secondary sensory cortices is necessary for remote cue-specific fear memory, and b) the postrhinal cortex mediates the context-dependency of extinction of remote cue-specific fear.