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疾病。大鼠基底外侧杏仁核 (BLA) 和边缘下 (IL) 前额皮质分别与消退获得和巩固有关，这两者都需要 NMDA 受体激活。我们最近发现，IL 神经元 NMDA 受体依赖性爆发中预先存在的差异可以预测灭绝的失败或成功。也就是说，IL爆发率较高的大鼠（2/3的大鼠）表现出成功的灭绝回忆，而IL爆发率较低的大鼠（1/3的大鼠）则未能回忆起灭绝。因此，少数老鼠无法回忆起灭绝事件可能代表了一种“创伤后应激障碍表型”。该模型具有表面有效性，因为只有少数遭受创伤的个体会继续发展 PTSD，这表明 IL 的兴奋性降低可能是一个诱发因素。然而，目前尚不清楚这种倾向的分子基础。脑源性神经营养因子 (BDNF) 是一种候选分子，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，并且阻断前额皮质中的 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 电流和下游信号传导可能是从药理学上预防 PTSD 表型的一种方法。 我们提出以下目标：1) 确定 IL 的基线（预处理）爆发率是否与灭绝成功程度相关，2) 确定 IL 的基线爆发是否与 BDNF 蛋白表达和 NMDA 受体磷酸化相关，3)尝试通过将 BDNF 直接施用到 IL 或 BLA 中来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面对创伤时的恢复能力较差，并可能为预防创伤后应激障碍的发展提供新的治疗方法。