PPARα对场景恐惧消退的调节以及其激动剂治疗创伤后应激障碍的研究

Post-traumatic stress disorder (PTSD) is characterized by the persistent and uncontrollable fear responses due to failure of fear extinction. However, lack of understanding the mechanisms underlying fear extinction prevents the development of targeted pharmacological interventions for this disease. Hippocampus, particularly, the dentate gyrus (DG) of the hippocampus, encodes fear associated contextual information and plays an important role in contextual fear memory acquisition, retrieval and extinction. Our previously study has found that adiponectin regulates DG granule neuron intrinsic excitability and promotes contextual fear extinction through one of its two major receptors, adipoR2. Literature show that activation of adipoR2 induces PPARα mediated gene transcription, independent of adipoR1 activation. PPARα is indeed expressed in the key brain regions that regulate contextual fear extinction, including dentate gyrus of the hippocampus. Therefore, we hypothesize that PPARα plays an important role in regulating contextual fear extinction through modulating DG excitability and PPARα agonist can be used as a targeted pharmacological treatment for PTSD. To test this hypothesis, we will use PPARα knockout mice as well as pharmacologically activation of PPARα to test the behavioral effects of PPARα activation on contextual fear extinction and the underlying electrophysiological mechanisms. This project will identify new molecular mechanism of contextual fear extinction and shine the light on using PPARα agonist as a novel pharmacological treatment for PTSD.

创伤后应激障碍（PTSD）的核心问题是恐惧消退失败造成的强烈、持续的恐惧反应。因此，对恐惧消退的生物学机理的研究是开发PTSD针对性治疗药物的关键。海马区是调节恐惧消退的主要脑区之一。海马齿状回（DG）神经元编码与恐惧相关联的场景信息并且参与调节场景恐惧消退。我们的前期工作发现，脂联素通过激活其在DG的受体2调节DG神经元兴奋性并促进场景恐惧消退。研究表明，脂联素通过受体2直接激活过氧化物酶体增殖物活化受体α（PPARα）。PPARα表达于海马区齿状回神经元并参与调节海马区功能。因此，我们假设，PPARα调节海马齿状回神经元兴奋性并促进场景恐惧消退。为验证以上假说，我们将使用PPARα敲除小鼠或核团注射PPARα激动剂，检测PPARα对DG神经元兴奋性和场景恐惧消退行为的调控。本项目将发现新的场景恐惧消退的分子生物学机理并开辟使用PPARα激动剂，如贝特类降脂药治疗PTSD的新方法。

创伤后应激障碍（PTSD）的核心问题是恐惧消退失败造成的强烈、持续的恐惧反应。因此，对恐惧消退的生物学机理的研究是开发PTSD针对性治疗药物的关键。海马区是调节恐惧消退的主要脑区之一。海马齿状回（DG）神经元编码与恐惧相关联的场景信息并且参与调节场景恐惧消退。我们的前期工作发现，脂联素通过激活其在DG的受体2调节DG神经元兴奋性并促进场景恐惧消退。研究表明，脂联素通过受体2直接激活过氧化物酶体增殖物活化受体α（PPARα）。PPARα表达于海马区齿状回神经元并参与调节海马区功能。因此，本项目对PPARα蛋白对场景恐惧消退的调节作用进行了系统研究，挖掘了其神经生物学机理并探索了PPARα蛋白激动剂对场景恐惧消退的调节作用。本研究在系统水平确认了PPARα对场景恐惧消退的调节作用，PPARα缺失导致严重场景恐惧消退障碍，使用CRISPR-Cas9技术在海马区齿状回特异性敲除PPARα蛋白，进而发现PPARα调节场景恐惧消退是通过对海马齿状回颗粒神经元功能进行的。进一步研究明确了PPARα蛋白缺失导致海马齿状回颗粒神经元自身兴奋性降低，使用PPARα蛋白激动剂A1增加海马齿状回神经元自身兴奋性并通过PPARα蛋白促进场景恐惧消退。本研究的完成发掘了场景恐惧消退的新的分子调控机制，为研发针对创伤后应激核心症状的有效治疗药物提供了坚实的神经生物学证据和突破口。