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）：大鼠的恐惧灭绝是一种适用于创伤后应激障碍（PTSD）的新兴情绪调节模型，这种疾病的特征是无法召回灭绝记忆。大鼠基底外侧杏仁核（BLA）和额叶前额叶皮层分别与灭绝和巩固有关，这两者都需要NMDA受体激活。我们最近发现，IL神经元的NMDA受体依赖性爆发预测的灭绝失败或成功的差异。也就是说，具有较高IL爆发率的大鼠（2/3的大鼠）表现出成功的灭绝召回，而爆发率较低的大鼠（1/3的大鼠）未能召回灭绝。因此，无法回忆少数大鼠的灭绝可能代表“ PTSD表型”。该模型具有面部有效性，因为只有少数暴露于创伤的人继续发展为PTSD，这表明IL兴奋性降低可能是一个诱人的因素。但是，目前尚不清楚这种易感性的分子基础。脑衍生的神经营养因子（BDNF）是一个分子候选者，可以解释IL生理学上存在的差异。 BDNF基因中的多态性与PTSD中存在的抑郁和焦虑有关。 BDNF还促进了NMDA受体功能，并且在额叶皮层中阻断NMDA受体足以在我们的大鼠模型中产生PTSD表型。使用BDNF来增强NMDA电流和下游信号传导可能是药理预防PTSD表型的一种手段。 我们提出以下目的：1）确定IL中的基线（预先条件）的破坏率是否与灭绝成功程度相关，2）确定IL中的基线爆发是否与BDNF蛋白表达和NMDA受体磷酸化以及3）试图通过PTSD photiption in a Blats in norder norder nortion或BLATS ptn formal blats bef be be nmda受体磷酸化以及3）。这项研究的发现可以解释为什么面对创伤时少数人的弹性较小，并且可以指向防止PTSD发展的新治疗方法。