Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder

Abstract

Post-traumatic stress disorder (PTSD) and other anxiety disorders stemming from dysregulated fear memory are problematic and costly. Understanding the molecular mechanisms that contribute to the formation and maintenance of these persistent fear associations is crucial to developing treatments for PTSD. Epigenetic mechanisms, which control gene expression to produce long-lasting changes in cellular function, may support the formation of fear memory underlying PTSD. We address here the role of epigenetic mechanisms in the formation, storage, updating, and extinction of fear memories. We also discuss methods of targeting these epigenetic mechanisms to reduce the initial formation of fear memory or to enhance its extinction. Epigenetic mechanisms may provide a novel target for pharmaceutical and other treatments to reduce aversive memory contributing to PTSD.

Keywords: PTSD; consolidation; epigenetics; extinction; fear conditioning; updating.

Figure 1

Fear conditioning, reconsolidation, and extinction procedures. A) Typical procedure for studying consolidation. Animals are trained with a neutral conditional stimulus (CS) that is paired with an aversive unconditional stimulus (UCS). Pictured, a tone CS is paired with a footshock UCS. Consolidation is usually tested by manipulating gene expression following training (arrow). 24h after training, tone fear is independently tested in a novel context (gray background) and context fear is assessed by returning the animal to the training chamber. Freezing is measured as an index of fear. B) Reconsolidation procedure. Usually, the tone CS is presented a single time in a novel context and gene expression is manipulated after the retrieval session. Fear to the CS is tested the following day. C) Extinction procedure, in which CS is repeatedly presented without the UCS. If extinction is properly acquired, the animal should show low tone freezing the following day at test. Arrows indicate appropriate time to perform manipulations. Lightning blot indicates UCS presentation.

Figure 2

Basic fear conditioning circuit. The amygdala (AMY) is the site of associative convergence between the tone or context CS and the footshock UCS. Output from the amygdala drives the fear response, including freezing. Individual context elements are formed into a configural “context” representation in the hippocampus (HPC) before being projected to the amygdala. The prelimbic mPFC (PL) also drives context fear during learning. During extinction, the infralimbic mPFC (IL) blocks amygdala output to block fear output. (Figures adapted from Allen Brain Atlas)[99].