Inhibition of Diacylglycerol Lipase Impairs Fear Extinction in Mice.

Victoria S Cavener,Puja Jagasia,Jashim Uddin,Lawrence J Marnett,Dante Pennipede,Sachin Patel,Andrew Gaulden

doi:10.3389/fnins.2018.00479

Victoria S Cavener, Puja Jagasia + Show 5 more

Open Access

https://doi.org/10.3389/fnins.2018.00479

Copy DOI

Abstract

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.

Highlights

Over the past 25 years, studies have shown that the endocannabinoid system is a key regulator of an organism’s response to stress and plays an important role in facilitating recovery after exposure to stress (Lutz et al, 2015; Patel et al, 2017; Hill et al, 2018)
Given that it has been previously shown that global DAGLα−/− mice exhibit impaired fear extinction (Jenniches et al, 2016), we first aimed to replicate these findings in our line of global DAGLα−/− mice in a fear conditioning and extinction protocol we and others have previously utilized extensively (Hartley et al, 2016) (Figure 1A)
There was no significant difference in freezing to tone during fear-conditioning on day 1 between DAGLα−/− and WT littermate controls (Figures 1B,C)

Summary

Introduction

Over the past 25 years, studies have shown that the endocannabinoid (eCB) system is a key regulator of an organism’s response to stress and plays an important role in facilitating recovery after exposure to stress (Lutz et al, 2015; Patel et al, 2017; Hill et al, 2018). Studies have shown that augmenting 2-AG reduces stress-induced anxiety-like and depressive-like behaviors and can promote resilience to the adverse effects of acute and repeated stress (Kinsey et al, 2011; Sciolino et al, 2011; Sumislawski et al, 2011; Roberts et al, 2014; Zhang et al, 2015; Bedse et al, 2017; Bluett et al, 2017; Heinz et al, 2017). 2-AG augmentation promotes the expression of conditioned freezing and impairs conditioned fear extinction learning (Llorente-Berzal et al, 2015; Hartley et al, 2016) This surprising contradiction highlights the complexity of eCB signaling in the brain and motivated us to further investigate the role of 2-AG signaling in the regulation of fear learning and extinction

Objectives

Methods

Results

Discussion

Conclusion