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

项目摘要 患有恐惧症的人，如创伤后应激障碍（PTSD）的经历 过度强烈和侵入性的恐惧记忆，关于在先前的刺激过程中遇到的刺激， 创伤，包括个人的声音或视觉刺激（“线索特异性”恐惧记忆）或 共同定义事件发生地点的刺激组合（“情境”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）， 在这种情况下，它们可能困扰一个人一生的相当大的一部分。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，大量的研究 已经确定了支持最近与远程上下文记忆的离散神经系统， 其他研究已经确定了最近获得的线索特异性记忆的基质， 灭绝，但很少有工作集中在大脑机制参与远程线索- 特定记忆和灭绝。这一点对于解决创伤后应激障碍尤其重要 由于个体通常在创伤事件发生后很久才寻求治疗， 战斗创伤或性侵犯为了解决这个问题，拟议的研究提出了一个新的 神经回路的理论模型，构成远程线索特定恐惧记忆的基础， 灭绝该模型基于我们实验室的新数据， 化学遗传学和光遗传学-解剖学方法来测试假设， 压后皮质和次级感觉皮质之间的通讯是必要的， B）嗅后皮层介导了情境依赖性 消除遥远的特定线索的恐惧。

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.