Hippocampal Role in Extinction Induced Prefrontal Plasticity

描述(申请人提供)：PTSD患者的功能成像研究表明，内侧前额叶皮质(MPFC)的激活减少导致了这些患者的过度恐惧反应和对治疗的反应受损。为了理解为什么创伤后应激障碍患者的mPFC活性较低，我们需要了解恐惧条件反射和消退改变mPFC活性的机制。对mPFC神经元的膜片钳记录显示，恐惧条件反射和消退可引起mPFC的内源性和突触变化。首先，IL神经元在恐惧条件反射后兴奋性降低，在消亡后兴奋性增强。抑制的IL兴奋性可降低IL的活性，增强条件性恐惧反应，而增强的IL兴奋性可导致相反的效果。与此一致，降低IL内在兴奋性可增强条件性恐惧反应并增加IL 兴奋性增强了恐惧反应的抑制。这些发现表明，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，来自PL的神经元在恐惧条件反射和消退后出现突触变化，而来自IL的神经元仅在消退后才出现突触变化。然而，mPFC神经元的输入在恐惧条件反射和消退后突触效能发生变化的身份仍不清楚。综上所述，这些发现表明，mPFC的内在和突触变化参与了恐惧条件反射和消退记忆的形成。这个建议的目的是通过研究腹侧海马区(VHPC)在恐惧条件反射和消退诱导的mPFC的内在和突触变化中的作用来扩展这些结果，因为消亡是上下文依赖的，vHPC通过与IL和PL的直接连接将这一关键的上下文信息传递给mPFC。在目标1中，我们将研究vHPC在调节IL的内在兴奋性变化中的作用。在目标2中，将评估vHPC在恐惧条件化和消退后的mPFC中介导突触可塑性的作用。这项研究的结果可能会对基于人类灭绝的暴露疗法产生重要影响，这种疗法通常是在不同于创伤经历的背景下进行的。

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.