Pre-existing Differences in BDNF and Fear Extinction

描述（由申请人提供）：大鼠恐惧消退是一种新兴的情绪调节模型，适用于创伤后应激障碍（PTSD），一种以无法回忆消退记忆为特征的疾病。大鼠基底外侧杏仁核（BLA）和边缘下前额叶皮层（IL）分别与消退获得和巩固有关，两者都需要NMDA受体激活。我们最近发现，先前存在的NMDA受体依赖性IL神经元爆发的差异预测了灭绝失败或成功。即，高IL爆发率的大鼠（2/3的大鼠）能够成功回忆起灭绝事件，而低IL爆发率的大鼠（1/3的大鼠）无法回忆起灭绝事件。因此，少数大鼠无法回忆起灭绝事件可能代表一种“创伤后应激障碍表型”。该模型具有表面有效性，因为只有少数暴露于创伤的个体继续发展为创伤后应激障碍，这表明IL兴奋性降低可能是一个诱发因素。然而，这种倾向的分子基础目前尚不清楚。脑源性神经营养因子（BDNF）是一种可能解释IL生理差异的候选分子。BDNF基因的多态性与PTSD患者的抑郁和焦虑有关。BDNF还促进NMDA受体的功能，阻断前额叶皮层的NMDA受体足以在我们的大鼠模型中产生PTSD表型。利用BDNF增强NMDA电流和下游信号可能是一种药理学上预防PTSD表型的手段。我们提出以下目标：1)确定IL的基线（预处理）破坏率是否与灭绝成功程度相关；2)确定IL的基线破裂是否与BDNF蛋白表达和NMDA受体磷酸化相关；3)通过将BDNF直接注入IL或BLA，试图减少正常大鼠群体中PTSD表型的发生。这项研究的发现可以解释为什么少数人在面对创伤时缺乏弹性，并可能为预防PTSD的发展指明新的治疗方法。

DESCRIPTION (provided by applicant): Fear extinction in rats is an emerging model of emotion regulation applicable to post-traumatic stress disorder (PTSD), a disorder characterized by an inability to recall extinction memory. The rat basolateral amygdala (BLA) and infralimbic (IL) prefrontal cortex have been implicated in extinction acquisition and consolidation, respectively, both of which require NMDA receptor activation. We recently discovered that pre-existing differences in the NMDA receptor-dependent bursting of IL neurons predicted extinction failure or success. Namely, rats with higher IL bursting rates (2/3 of rats) exhibited successful extinction recall, while rats with low bursting rates (1/3 of rats) failed to recall extinction. Thus, the inability to recall extinction in a minority of rats may represent a "PTSD phenotype." This model has face validity, as only a minority of trauma-exposed individuals goes on to develop PTSD, suggesting that decreased excitability in IL may be a predisposing factor. The molecular basis for this predisposition, however, is currently unknown. Brain derived neurotrophic factor (BDNF) is one molecular candidate that may explain pre-existing differences in IL physiology. Polymorphisms in the BDNF gene have been linked to depression and anxiety, which are present in PTSD. BDNF also facilitates NMDA receptor function, and blocking NMDA receptors in prefrontal cortex is sufficient to produce the PTSD phenotype in our rat model. Using BDNF to enhance NMDA currents and downstream signaling may be a means of pharmacologically preventing the PTSD phenotype. We propose the following aims: 1) Determine if baseline (pre-conditioning) busting rates in IL correlate with the degree of extinction success, 2) Determine if baseline bursting in IL is correlated with BDNF protein expression and NMDA receptor phosphorylation, and 3) Attempt to reduce the occurrence of the PTSD phenotype in a normal population of rats by administering BDNF directly into IL or BLA. The findings from this study could explain why a minority of individuals are less resilient in the face of trauma, and could point towards new treatments for preventing the development of PTSD.