Cedomir Todorovic, NMDA-JNK signaling mediate Fear Memory Elimination


Post-Traumatic Stress Disorder (PTSD) is an anxiety disorder induced by exposure to extreme stress. The treatment of choice for PTSD is extinction-based exposure psychotherapy. Experimental studies of extinction show that when previously conditioned animals are re-exposed to the conditioned stimulus (CS) in absence of the unconditioned stimulus (US), previously acquired responses gradually decline. However, in PTSD, extinction mechanisms are often incomplete, and successful fear reduction through exposure therapy is often accompanied by sudden bouts of fear reoccurrence (Myers et al., 2011; Rauch et al., 2006; Brewin, 2008).

The main objective of this research is to test the hypothesis that immediate impairment of original traumatic memories rather than extinction of the fear response generated from those memories is a more effective strategy to counter PTSD. The possibility that memory is prone to impairment is based on the idea that memory relies on bidirectional synaptic modification, and that changes in synaptic weights generated by traumatic learning experience are reversible (Heynen et al, 2000; Clem and Huganir, 2010).

In my laboratory, we have established a mouse behavioral model for testing acquisition and extinction of memory associated with fear and trauma. Our recent work suggests that the hippocampal c-Jun-N-terminal kinase 3 (JNK3) pathway is involved in impairment of contextual fear memories (Sherrin et al., 2010). Others have shown that modulation of N-methyl-D-aspartate receptor (NMDAR) function in the amygdala by a partial agonist D-cycloserine (DCS) facilitates extinction (Myers et al., 2011) or leads to permanent elimination of simple conditioned fear responses (Mao et al., 2006). However, there is no information about the role of hippocampal NMDA receptors or JNK signaling in extinction of contextual fear.

Therefore, the main goal of this application is to investigate whether the DCS-mediated elimination of contextual conditioned fear memory results from modulation of hippocampal NMDA receptors that leads to activation of a JNK signaling pathway, which in turn initiates changes in synaptic AMPA receptor distribution. To achieve this goal, we will employ a combination of molecular, electrophysiological, and behavioral assays