Cellular mechanisms mediating extinction of conditioned fear

描述(申请人提供)：焦虑症，包括恐慌、恐惧症、创伤后应激障碍、强迫症和广泛性焦虑，是最常见的精神疾病形式。研究表明，至少有一些焦虑症与大脑的恐惧系统有关。一个人对某一创伤性事件的有意识记忆可能非常差，但同时通过恐惧条件反射机制可以形成非常强烈的无意识情绪记忆。这些对灭绝恐惧的抵抗力可能会成为强烈焦虑的来源。要完全理解这种病理状态的病因，需要详细了解恐惧相关行为的神经机制，特别是提供恐惧消退神经底物的可塑性修饰的性质。这最终可能被转化为治疗焦虑和治疗抗药性恐惧症的临床环境。恐惧条件作用训练范式非常适合于恐惧学习和恐惧消退的细胞和分子研究。我们的研究以及其他实验室之前的发现表明，学习背后的神经元可塑性可以在切片制备中直接确定，然后与实验动物的行为状态相关。在这里，我们提出了一项行为和电生理相结合的研究，以解决有关条件性恐惧消退背后的神经回路中可塑性修饰的性质的具体问题。在目标1中，我们将探讨与条件性恐惧消退相关的杏仁核外侧核、基底核和中央核投射到mPFC的边缘下部神经元的内在兴奋性的变化。我们的方法是从灭绝训练后不同时间点的脑片中mPFC边缘下部逆行标记的神经元获得全细胞膜片钳记录。在目标2中，我们将分析恐惧消退对恐惧条件化和恐惧消除大鼠脑片杏仁核外侧核和基底核中间神经元GABA抑制性神经传递和内源性兴奋性的影响。这些实验将阐明塑料修饰的本质，它可能为恐惧消退提供神经基础。更好地了解恐惧消退的细胞机制将有助于合理开发治疗广泛性焦虑和创伤后应激障碍(PTSD)或其他涉及大脑恐惧系统的疾病的新疗法。与公共健康相关：拟议中的研究将提高我们对恐惧记忆消退背后的细胞机制的理解。更好地了解恐惧相关行为的细胞机制将有助于合理开发治疗创伤后应激障碍(PTSD)和广泛性焦虑的新疗法。

DESCRIPTION (provided by applicant): Anxiety disorders, which include panic, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, and generalized anxiety, are among the most common forms of mental illness. It was suggested that at least some anxiety disorders involve the fear system of the brain. An individual can have very poor conscious memory of a certain traumatic event, but at the same time very strong unconscious emotional memories could be formed through fear conditioning mechanisms. These very resistant to extinction fears can become a source of intense anxiety. A complete understanding of etiology of such pathological conditions requires detailed information about the neuronal mechanisms of fear-related behaviors and, specifically, about the nature of plastic modifications that provide the neural substrate of fear extinction. This could be translated eventually to the clinical setting for the treatment of anxiety and therapy-resistant phobias. Fear conditioning training paradigm is well suited for the cellular and molecular studies of fear learning and fear extinction. Our studies, as well as previous findings from other laboratories, indicate that neuronal plasticity underlying learning can be directly determined in the slice preparation and then correlated to the behavioral status of the experimental animal. Here we propose a combined behavioral and electrophysiological study to address specific questions concerning the nature of plastic modifications in the neural circuitry underlying extinction of conditioned fear. In Aim 1, we will explore the changes in intrinsic excitability of neurons in the infralimbic division of the mPFC projecting to the lateral, basal and central nuclei of the amygdala associated with extinction of conditioned fear. Our approach will be to obtain whole-cell patch clamp recordings from retrogradely labeled neurons in the infralimbic division of the mPFC in brain slices at different time points after extinction training. In Aim 2, we will analyze the effects of fear extinction on GABAeric inhibitory neurotransmission and intrinsic excitability of interneurons in the lateral and basal nuclei of the amygdala in slices from fear conditioned and fear-extinguished rats. These experiments will elucidate the nature of plastic modifications which may provide a neural substrate of fear extinction. A better understanding of the cellular mechanisms of fear extinction will permit the rational development of novel therapeutic treatments for generalized anxiety and posttraumatic stress disorder (PTSD) or other illnesses implicating the fear system of the brain. PUBLIC HEALTH RELEVANCE : The proposed studies will improve our understanding of the cellular mechanisms underlying extinction of fear memory. A better knowledge of the cellular mechanisms of fear-related behavior will permit the rational development of novel therapeutic treatments for posttraumatic stress disorder (PTSD) and generalized anxiety.