Synaptic mechanisms in extinction of conditioned fear

描述（由申请人提供）：皮层-杏仁核和丘脑-杏仁核通路中的长时程增强（LTP）样突触增强有助于对听觉刺激的恐惧记忆的获得。当条件刺激（CS）反复不加强时，条件性恐惧反应可以减弱甚至消除，从而导致恐惧消退。然而，条件恐惧的消失并不反映在杏仁核中形成的原始cs -非条件刺激（US）关联的“遗忘”，而是可能涉及抑制条件恐惧记忆检索的新关联的形成。这表明在消退训练后，由恐惧学习引起的突触增强在CS通路中可能被保留。然而，最近几项实验和模型研究的结果表明，在某些条件下，恐惧条件反射增强的听觉输入中突触强度的去电位样降低可能有助于条件性恐惧的消除，这表明不能排除与消除相关的突触修饰的作用。在这里，我们提出了一项结合行为和电生理的研究，旨在解决与恐惧消退相关的CS通路中塑料修饰的性质的具体问题。在目的1中，我们将描述皮层和丘脑输入与条条性恐惧消退相关的LA的突触修饰。我们将在复合和单一突触电流水平上，对在恐惧条件反射训练范式中训练和熄灭（条件反射后30分钟或24小时）的大鼠切片进行皮质-杏仁核和丘脑-杏仁核通路的突触传递。Aim 2将探讨皮层和丘脑输入去增强的突触机制，并将其与条件恐惧消退引起的突触变化进行比较。通过研究这些机制，并将其与与恐惧消退相关的行为诱导可塑性机制（如Aim 1中提出的）以及恐惧条件化大鼠切片（在30分钟和24小时后）的去增强诱导刺激效果进行比较，我们将解决一个问题，即在切片中经历LTP的突触反应的去增强和可能涉及条件恐惧消除的突触可塑性是否在机制上相似。这些实验将阐明条件刺激通路中突触修饰的本质，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，将有助于合理开发新的焦虑障碍治疗方法。它还可以帮助优化导致创伤后应激障碍（PTSD）患者抑制不想要的记忆的治疗方法。

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.