Synaptic mechanisms in extinction of conditioned fear

描述（由申请人提供）：皮质-杏仁核和丘脑-杏仁核通路中的长时程增强（LTP）样突触增强有助于获得对听觉刺激的恐惧记忆。当条件刺激（CS）被反复非强化时，条件恐惧反应可以被减弱甚至消除，导致恐惧消退。灭绝的条件恐惧，但是，并不反映'unlearning'的原始CS-无条件刺激（US）协会在杏仁核中形成，但可能涉及到新的协会抑制检索条件恐惧记忆的形成。这表明，恐惧学习诱导的突触增强CS通路可能会保留后灭绝训练。然而，最近的几个实验和建模研究的结果表明，在听觉输入到LA的突触强度的降压样下降，增强恐惧条件反射，可能有助于在某些条件下的条件恐惧的灭绝，这表明不能排除的预防相关的突触修饰的作用。在这里，我们提出了一个联合的行为和电生理学研究，旨在解决具体的问题，在CS通路与恐惧灭绝相关的塑料修改的性质。在目标1中，我们将描述与条件恐惧消退相关的LA的皮层和丘脑输入的突触修饰。我们将在复合和单一突触电流的水平上研究在恐惧条件训练范式中训练和熄灭（条件训练后30分钟或24小时）的大鼠脑片中皮质-杏仁核和丘脑-杏仁核通路的突触传递。目的2将探讨皮层和丘脑输入去增强的突触机制，并将其与条件性恐惧消退引起的突触变化进行比较。通过调查这些机制并将其与与恐惧消退相关的行为诱导可塑性机制进行比较（如目标1中所提出的），以及恐惧条件大鼠切片中去电位诱导刺激的作用（在调节后30分钟和24小时），我们将讨论一个问题，即在脑片中经历LTP的突触反应的去增强和突触可塑性是否可能参与了LTP的形成。消除条件性恐惧的机制是相似的。这些实验将阐明条件刺激通路中突触修饰的性质，这可能有助于恐惧消退。更好地理解恐惧条件反射神经回路中突触可塑性的基本机制将允许合理开发焦虑症的新治疗方法。它还可以帮助优化治疗，从而抑制创伤后应激障碍（PTSD）患者不想要的记忆。 公共卫生相关性：这些研究对于我们理解杏仁核中与恐惧条件反射和恐惧消退相关的突触可塑性机制具有重要意义。更好地了解恐惧条件反射和消退的细胞机制将允许合理开发焦虑症的新治疗方法。它还可以帮助优化创伤后应激障碍（PTSD）患者的治疗。

DESCRIPTION (provided by applicant): Long-term potentiation (LTP)-like synaptic enhancements in cortico-amygdala and thalamo-amygdala pathways contribute to the acquisition of fear memory to auditory stimulation. The conditioned fear response can be diminished or even eliminated when the conditioned stimulus (CS) is repeatedly non-reinforced, resulting in fear extinction. Extinction of conditioned fear, however, does not reflect 'unlearning' of the original CS-unconditioned stimulus (US) association formed in the amygdala but may involve the formation of new associations inhibiting retrieval of conditioned fear memory. This indicates that fear learning-induced synaptic enhancements in the CS pathways might be retained following extinction training. Nevertheless, the results of several recent experimental and modeling studies suggest that depotentation-like decreases of synaptic strength in auditory inputs to the LA, potentiated by fear conditioning, could contribute to extinction of conditioned fear under certain conditions, indicating that the role of extinction-associated synaptic modifications could not be ruled out. Here we propose a combined behavioral and electrophysiological study aiming to address specific questions concerning the nature of plastic modifications in the CS pathways associated with fear extinction. In Aim 1, we will characterize synaptic modifications in cortical and thalamic inputs to the LA associated with extinction of conditioned fear. We will examine synaptic transmission in both cortico-amygdala and thalamo-amygdala pathways in slices from rats trained and extinguished (at 30 min or 24 hr following conditioning) in fear conditioning training paradigm at the level of compound and unitary synaptic currents. In Aim 2 will explore synaptic mechanisms of depotentiation in cortical and thalamic inputs and compare them to synaptic changes induced by extinction of conditioned fear. By investigating these mechanisms and comparing them to the mechanisms of behavior-induced plasticity associated with fear extinction (as proposed in Aim 1), and to the effects of depotentiation-inducing stimulation in slices from fear- conditioned rats (at 30 min and 24 hr post-conditioning), we will address a question whether depotentiation of synaptic responses undergoing LTP in slices and synaptic plasticity which might be involved in extinction of conditioned fear are mechanistically similar. These experiments will illuminate the nature of synaptic modifications in the conditioned stimulus pathways, which may contribute to fear extinction. A better understanding of the basic mechanisms of synaptic plasticity in the neural circuit of fear conditioning will permit the rational development of novel therapeutic treatments for anxiety disorders. It could also help to optimize the treatments leading to suppression of unwanted memories in posttraumatic stress disorder (PTSD) patients. PUBLIC HEALTH RELEVANCE: These studies are important to our understanding the mechanisms of synaptic plasticity in the amygdala in relation to fear conditioning and fear extinction. A better knowledge of the cellular mechanisms of fear conditioning and extinction will permit the rational development of novel therapeutic treatments for anxiety disorders. It could also help to optimize the treatments of postraumatic stress disorder (PTSD) patients.