Hippocampal Role in Extinction Induced Prefrontal Plasticity

描述（由申请人提供）：PTSD患者的功能成像研究表明，内侧前额叶皮层（mPFC）的激活减少导致过度恐惧反应，并导致这些患者对治疗的反应受损。为了理解为什么mPFC在PTSD患者中激活较少，我们需要了解恐惧条件反射和消退改变mPFC活性的机制。膜片钳记录的mPFC神经元，填充前边缘（PL）和边缘下（IL）皮质，揭示了大鼠的恐惧条件反射和灭绝诱导内在和突触的变化mPFC。首先，IL神经元表现出恐惧条件反射后兴奋性降低，而消退后兴奋性增强。抑制IL兴奋性可降低IL激活，增强条件性恐惧反应，而增加IL兴奋性则相反。与此相一致，降低IL内在兴奋性增强了条件性恐惧反应，增加IL 兴奋性增强恐惧反应抑制。这些发现意味着IL的内在兴奋性状态是恐惧表达水平的决定因素之一。第二，PL的神经元在恐惧条件化和消退后显示突触变化，而IL的神经元仅在消退后显示突触变化。然而，到mPFC神经元的输入的身份表现出的变化后，恐惧条件反射和灭绝的突触功效仍然未知。两者合计，这些研究结果表明，内在的和突触的变化，在mPFC介导的恐惧条件反射和灭绝记忆的形成。本提案的目标是通过检查腹侧海马（vHPC）在这些恐惧条件反射和恐惧诱发的mPFC内在和突触变化中的贡献来扩展这些结果，因为灭绝是上下文相关的，vHPC通过与IL和PL的直接连接将这一重要的上下文信息传递给mPFC。在目的1中，将检查vHPC在介导IL的内在兴奋性变化中的作用。在目标2中，将评估vHPC在恐惧条件反射和消退后介导mPFC中的突触可塑性中的作用。这项研究的结果可能对人类基于预防的暴露疗法具有重要意义，这种疗法通常是在与创伤经历不同的背景下进行的。

DESCRIPTION (provided by applicant): Functional imaging studies in PTSD patients suggest that reduced activation of the medial prefrontal cortex (mPFC) contributes to the excessive fear response and to the impaired response to treatment seen in these patients. To understand why the mPFC is less activated in PTSD patients, we need to understand the mechanisms by which fear conditioning and extinction alter mPFC activity. Patch-clamp recordings of mPFC neurons, which populate the prelimbic (PL) and infralimbic (IL) cortices, revealed that fear conditioning and extinction in rats induces intrinsic and synaptic changes in the mPFC. First, IL neurons showed decreased excitability after fear conditioning, and enhanced excitability after extinction. The depressed IL excitability could reduce IL activation and enhance conditioned fear responses, whereas the increased IL excitability could result in the opposite effect. Consistent with this, reducing IL intrinsic excitability enhances conditioned fear responses and increasing IL excitability enhances fear response inhibition. These findings imply that the intrinsic excitabilit state of IL is one determinant of the level of fear expression. Second, neurons from PL showed synaptic changes after fear conditioning and extinction, whereas neurons from IL showed synaptic changes only after extinction. However, the identities of the inputs onto mPFC neurons exhibiting changes in synaptic efficacy after fear conditioning and extinction remain unknown. Taken together, these findings suggest that intrinsic and synaptic changes in the mPFC mediate the formation of fear conditioning and extinction memory. The goal of this proposal is to extend these results by examining the contribution of the ventral hippocampus (vHPC) in these fear conditioning- and extinction-induced intrinsic and synaptic changes in the mPFC, since extinction is context-dependent and the vHPC conveys this crucial contextual information to the mPFC via direct connections to IL and PL. In Aim 1, the role of the vHPC in mediating intrinsic excitability changes in IL will be examined. In Aim 2, the role of the vHPC in mediating synaptic plasticity in the mPFC after fear conditioning and extinction will be evaluated. The results of thi study could have important implications for human extinction-based exposure therapy, which is generally done in a context that is different from the context of the traumatic experience.