Pre-existing Differences in BDNF and Fear Extinction

BDNF 和恐惧消退预先存在的差异

• 批准号: 7613259
• 负责人: JAMIE PETERS
• 金额: $ 3.77万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-11-16 至 2009-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613259
• 关键词: Accounting; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Brain-Derived Neurotrophic Factor; Condition; Data; Development; Disease; Exhibits; Extinction (Psychology); Face; Failure; Fright; Genes; Genetic Polymorphism; Goals; Histone Acetylation; Human; Individual; Injection of therapeutic agent; Intervention; Lead; Link; Measures; Medial; Memory; Mental Depression; Minority; Mitogen Receptors; Mitogen-Activated Protein Kinases; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Patients; Phenotype; Phosphorylation; Physiology; Population; Post-Traumatic Stress Disorders; Predisposing Factor; Predisposition; Prefrontal Cortex; Protein Biosynthesis; Proteins; Rate; Rattus; Receptor Activation; Rodent; Screening procedure; Signal Transduction; Stress; Testing; Training; Trauma; War; base; classical conditioning; conditioned fear; conditioning; emotion regulation; experience; learning extinction; neuronal excitability; prevent; promoter; protein expression; psychologic; receptor function; repaired; research study; response; success

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.

描述（由申请人提供）：大鼠的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障碍。大鼠基底外侧杏仁核（BLA）和边缘下（IL）前额叶皮层已被牵连在灭绝收购和巩固，分别，这两个需要NMDA受体激活。我们最近发现，IL神经元的NMDA受体依赖性爆发中预先存在的差异可以预测灭绝失败或成功。即，具有较高IL爆发率的大鼠（2/3的大鼠）表现出成功的消退回忆，而具有低爆发率的大鼠（1/3的大鼠）未能回忆消退。因此，在少数大鼠中不能回忆起灭绝可能代表了“创伤后应激障碍表型”。“这个模型具有表面有效性，因为只有少数创伤暴露的个体会继续发展PTSD，这表明IL的兴奋性降低可能是一个诱发因素。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）是一种分子候选者，可以解释IL生理学中预先存在的差异。BDNF基因的多态性与PTSD中存在的抑郁和焦虑有关。BDNF还促进NMDA受体功能，阻断前额叶皮层中的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预防PTSD表型的一种手段。 我们提出以下目标：1）确定IL中的基线（预处理）爆发率是否与消退成功的程度相关，2）确定IL中的基线爆发是否与BDNF蛋白表达和NMDA受体磷酸化相关，和3）通过将BDNF直接施用到IL或BLA中来尝试减少正常大鼠群体中PTSD表型的发生。这项研究的结果可以解释为什么少数人在面对创伤时弹性较低，并可能指向预防PTSD发展的新治疗方法。