Cavener Victoria S, Gaulden Andrew, Pennipede Dante, Jagasia Puja, Uddin Jashim, Marnett Lawrence J, Patel Sachin
Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States.
Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States.
Front Neurosci. 2018 Jul 31;12:479. doi: 10.3389/fnins.2018.00479. eCollection 2018.
Elucidating the underlying molecular mechanisms regulating fear and extinction learning may offer insights that can lead to novel treatments for debilitating anxiety and trauma-related disorders including posttraumatic stress disorder. The endocannabinoid (eCB) system is a retrograde inhibitory signaling pathway involved in regulating central responses to stress. The eCB 2-arachidonoylglycerol (2-AG) has recently been proposed to serve as a homeostatic signal mitigating adverse effects of stress exposure, however, less well understood is 2-AG's role in fear learning and fear extinction. In this study, we have sought to explore 2-AG's role in fear conditioning and fear extinction by disrupting 2-AG synthesis utilizing the DAGL inhibitor (DO34) and DAGLα knock-out mice (DAGLα). We found that DAGLα mice, and male and female C57B6/J mice treated with DO34, exhibited impairment in extinction learning in an auditory cue fear-conditioning paradigm. DO34 did not increase unconditioned freezing. Interestingly, inhibition of fatty-acid amide hydrolase was not able to restore normal fear extinction in DO34-treated mice suggesting increased Anandamide cannot compensate for deficient 2-AG signaling in the regulation of fear extinction. Moreover, augmentation of CB1R signaling with tetrahydrocannabinol also failed to restore normal fear extinction in DO34-treated mice. Overall, these data support the hypothesis that DAGLα plays an important role in fear extinction learning. Although genetic and pharmacological disruption of DAGL activity causes widespread lipidomic remodeling, these data combined with previous studies putatively suggest that deficient 2-AG signaling could be a susceptibility endophenotype for the development of trauma-related psychiatric disorders.
阐明调节恐惧和消退学习的潜在分子机制，可能会为治疗使人衰弱的焦虑症和创伤相关疾病（包括创伤后应激障碍）带来新的治疗方法。内源性大麻素（eCB）系统是一种逆行抑制信号通路，参与调节对压力的中枢反应。最近有人提出，eCB 2-花生四烯酸甘油酯（2-AG）可作为一种稳态信号，减轻应激暴露的不良影响，然而，2-AG在恐惧学习和恐惧消退中的作用尚不清楚。在本研究中，我们试图通过使用二酰甘油脂肪酶（DAGL）抑制剂（DO34）和DAGLα基因敲除小鼠（DAGLα）破坏2-AG的合成，来探索2-AG在恐惧条件反射和恐惧消退中的作用。我们发现，DAGLα小鼠以及用DO34处理的雄性和雌性C57B6/J小鼠，在听觉线索恐惧条件反射范式中表现出消退学习障碍。DO34并没有增加无条件僵住反应。有趣的是，抑制脂肪酸酰胺水解酶并不能恢复DO34处理小鼠的正常恐惧消退，这表明增加的花生四烯乙醇胺不能补偿2-AG信号在调节恐惧消退中的不足。此外，用四氢大麻酚增强CB1R信号也不能恢复DO34处理小鼠的正常恐惧消退。总体而言，这些数据支持了DAGLα在恐惧消退学习中起重要作用的假设。虽然DAGL活性的基因和药理学破坏会导致广泛的脂质组重塑，但这些数据与先前的研究相结合，推测2-AG信号不足可能是创伤相关精神疾病发展的一种易感性内表型。
