Examination Date

6-9-2022

Degree

Dissertation

Degree Program

Cell Biology and Anatomy

Examination Committee

S. June Liu, Matthew Whim, Hamilton Farris, Xiaolin Tian, Nicholas Gilpin, Scott Edwards

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder characterized by intrusive memories among other symptoms. Fear conditioning is an associative learning paradigm used as an animal model for PTSD. The cerebellum is a brain region involved in cognitive processes. Endocannabinoids are important regulators of learning induced plasticity. A recent publication from our lab showed that fear conditioning accelerates endocannabinoid degradation through monoacyl glycerol lipase (MAGL), which lowers tonic endocannabinoid signaling, and this is required for memory consolidation. MAGL is an enzyme that degrades 2-arachidonoylglycerol (2-AG), which is a major endocannabinoid in the cerebellum. In this study, we investigate the mechanisms underlying learning-induced increase in MAGL expression.

Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that binds to the promoter region of the MAGL gene and enhances its transcription. We hypothesize that the fear conditioning-induced increase in MAGL expression is mediated by PPARα. We show that fear conditioning leads to an increase in MAGL activity in lobules V/VI of cerebellum, a region critical for memory consolidation. We next tested if PPARα antagonism could prevent the fear conditioning-induced increase in MAGL activity, expression, and subsequent reduction in endocannabinoid signaling. In mice, GW6471, a PPARα antagonist, administration 30 minutes prior to fear conditioning prevents learning induced increase in MAGL activity and expression in lobules V/VI. Using in vitro electrophysiology, we found that GW6471 pretreatment prevented the learning-induced decrease in endocannabinoid signaling. We further determined the impact of PPARα antagonist administration on fear memory consolidation and found that GW6471 injection impaired cued memory retention. These findings show that fear conditioning enhances MAGL activity via a PPARα -dependent pathway that reduces endocannabinoid tone, promoting memory consolidation.

Alcohol can act as a PPARα antagonist by reducing its binding to DNA. We tested if alcohol exposure reduces MAGL activity and impairs fear memory. We found that chronic, but not acute alcohol exposure reduces MAGL activity. Acute alcohol exposure via vapor and intraperitoneal injection did not impair fear memory. PPARα’s ability to mediate learning induced increase in MAGL activity, expression, and subsequent reduction in endocannabinoid signaling make it an excellent target in shaping learned behaviors.

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