Mechanisms of short and long interval fear extinction

描述（由申请人提供）：当一个恐惧条件生物体在没有任何厌恶事件的情况下反复暴露于引发恐惧的线索时，条件性恐惧反应会下降并最终消失。这个过程被称为恐惧消退。在大多数情况下，消失被认为是对恐惧的抑制，但如果在恐惧获得后不久进行消失训练，消失可能包括消除恐惧。因此，比较短时间（10分钟）和长时间（72小时）的间隔消失可以用来阐明恐惧抑制与恐惧消除的神经生物学机制。初步数据表明NMDA受体的不同参与：p44/42 MAPK和NMDA受体NR2B（但不是NR1）亚基的表达在10分钟消失后杏仁核内减少，10分钟消失不受NMDA受体拮抗剂的影响，而72小时消失被阻断。理解这个问题对于推进对学习和记忆的神经生物学的理解以及从临床角度来说都是重要的。本提案旨在结合生物化学和药理学技术来剖析作为抑制与消除恐惧的消退机制。

DESCRIPTION (provided by applicant): When a fear conditioned organism is exposed repeatedly to a fear-eliciting cue in the absence of any aversive event, the conditioned fear response declines and ultimately disappears. This process is known as fear extinction. In most cases extinction is believed to represent inhibition of fear, but extinction may involve erasure of fear if extinction training occurs very shortly after fear acquisition. Therefore, comparison of short (10 min) and long (72 hr) interval extinction may be used to elucidate the neurobiological mechanisms of fear inhibition vs. fear erasure. Preliminary data suggest differential involvement of NMDA receptors: expression of p44/42 MAPK and the NR2B (but not NR1) subunit of the NMDA receptor decreases within the amygdala following 10 min extinction, and 10 min extinction is not affected by administration of an NMDA receptor antagonist whereas 72 hr extinction is blocked. Understanding this issue will be important in terms of advancing understanding of the neurobiology of learning and memory, as well as from a clinical perspective. This proposal aims to employ a combination of biochemical and pharmacologic techniques to dissect the mechanisms of extinction as inhibition vs. erasure of fear.