Prefrontal-Amygdala Interactions in Fear Extinction

描述（由申请人提供）：当恐惧和焦虑等情绪不受控制时，会产生一些对身心健康有害的行为。这种使人衰弱的特征是焦虑症的特征，如创伤后应激障碍（PTSD）。情绪调节的生物标记可以在涉及巴甫洛夫恐惧条件反射和消退的动物模型中理解。恐惧消退发生在当一个音调，已经提出了一个厌恶的刺激是重复提出在没有刺激。在人类中，无法消除恐惧反应被认为是导致创伤后应激障碍和其他焦虑症的原因。灭绝，作为一个学习过程，需要三个阶段：获取，巩固和检索。最近来自啮齿动物研究的证据表明内侧前额叶皮层（mPFC）和基底外侧杏仁核（BLA）在灭绝中。然而，目前还不清楚这些结构在灭绝过程中何时以及如何相互作用。在目标1中，我们将确定在哪些阶段的消退训练mPFC和BLA是必要的。这将通过以下方式实现：1）在消退训练的不同阶段，mPFC可逆失活; 2）在消退训练的不同阶段，BLA可逆失活。一旦确定了BLA-mPFC相互作用的关键阶段，目标2将评估BLA在消退期间对IL中的音调诱发和自发神经元活动的贡献。这将通过BLA的可逆失活来实现，同时记录消退期间mPFC中的神经元活动。理解恐惧消退所必需的结构的相互作用可以阐明情绪调节的机制。这些机制的缺陷可能是PTSD和其他焦虑症的潜在因素。 公共卫生相关性：在人类中，无法消除恐惧反应被认为是焦虑症和创伤后应激障碍（PTSD）的潜在因素。这项研究旨在了解灭绝所需的神经结构如何以及何时相互作用。杏仁核和前额叶皮层之间的生理机制的缺陷可以被挽救，从而减少灭绝失败。这可能会导致基于预防的PTSD治疗的新疗法。

DESCRIPTION (provided by applicant): When emotions such as fear and anxiety are unregulated, several behaviors develop that are detrimental to mental and physical health. Such debilitating features are characteristic of anxiety disorders like post-traumatic stress disorder (PTSD). Biological markers of emotional regulation can be understood in an animal model involving Pavlovian fear conditioning and extinction. Fear extinction occurs when a tone that had been presented with an aversive stimulus is repeatedly presented in the absence of the stimulus. In humans, failure to extinguish fear responses is thought to contribute to PTSD and other anxiety disorders. Extinction, as a learning process, requires three phases: acquisition, consolidation, and retrieval. Recent evidence from rodent studies implicates the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in extinction. It is unclear, however, when and how these structures interact during extinction. In Aim 1, we will determine in which phases of extinction training mPFC and BLA is necessary. This will be achieved by: 1) reversible inactivation of mPFC during different phases of extinction training; 2) reversible inactivation of BLA during different phases of extinction training. Once the critical phase of BLA-mPFC interaction is determined, Aim 2 will assess the contribution of BLA to tone-evoked and spontaneous neuronal activity in IL during extinction. This will be achieved by reversible inactivation of BLA while simultaneously recording neuronal activity in mPFC during extinction. Understanding the interaction of structures necessary for fear extinction could elucidate the mechanisms of emotional regulation. Deficiencies in these mechanisms may be the underlying factors in PTSD and other anxiety disorders. PUBLIC HEALTH RELEVANCE: In humans, the inability to extinguish fear responses is believed to be an underlying factor of anxiety disorders and post-traumatic stress disorder (PTSD). This research aims to understand how and when neural structures necessary for extinction interact. Deficiencies in the physiological mechanisms between the amygdala and prefrontal cortex could be rescued, thus reducing extinction failure. This could lead to novel treatments for extinction-based therapies for PTSD.