Pre-existing Differences in BDNF and Fear Extinction

描述(申请人提供)：大鼠的恐惧消退是适用于创伤后应激障碍(PTSD)的一种新兴的情绪调节模型，PTSD是一种以无法回忆消退记忆为特征的障碍。大鼠杏仁基底外侧核(BLA)和下缘(IL)前额叶皮质分别与消退习得和巩固有关，两者都需要NMDA受体激活。我们最近发现，依赖NMDA受体的IL神经元爆发的预先存在的差异预示着灭绝、失败或成功。也就是说，IL爆发率较高的大鼠(2/3)表现出成功的灭绝回忆，而低爆发率的大鼠(1/3的大鼠)未能回忆起灭绝。因此，少数大鼠无法回忆起灭绝可能代表了一种“创伤后应激障碍表型”。这个模型在表面上是正确的，因为只有少数创伤暴露的个体继续发展为创伤后应激障碍，这表明IL的兴奋性降低可能是一个易感因素。然而，这种易感性的分子基础目前尚不清楚。脑源性神经营养因子(BDNF)是可能解释先前存在的IL生理学差异的一个候选分子。BDNF基因的多态与抑郁和焦虑有关，而抑郁和焦虑存在于创伤后应激障碍。BDNF还促进NMDA受体的功能，阻断前额叶皮质的NMDA受体足以在我们的大鼠模型中产生PTSD表型。使用BDNF增强NMDA电流和下游信号可能是从药物上预防PTSD表型的一种手段。我们提出了以下目标：1)确定IL基线(预适应)破损率是否与消退成功程度相关，2)确定IL基线破损率是否与BDNF蛋白表达和NMDA受体磷酸化相关，3)试图通过将BDNF直接注入IL或BLA来减少正常大鼠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韧性较差，并可能为预防创伤后应激障碍的发展提供新的治疗方法。

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.