Fear extinction in rats is an emerging model of emotion regulation applicable to post-traumatic stress disorder (PTSD), a disorder characterized by an inability to recall extinction memory. The rat basolateral amygdala (BLA) and infralimbic (IL) prefrontal cortex have been implicated in extinction acquisition and consolidation, respectively, both of which require NMDA receptor activation. We recently discovered that pre-existing differences in the NMDA receptor-dependent bursting of IL neurons predicted extinction failure or success. Namely, rats with higher IL bursting rates (2/3 of rats) exhibited successful extinction recall, while rats with low bursting rates (1/3 of rats) failed to recall extinction. Thus, the inability to recall extinction in a minority of rats may represent a """"""""PTSD phenotype."""""""" This model has face validity, as only a minority of trauma-exposed individuals goes on to develop PTSD, suggesting that decreased excitability in IL may be a predisposing factor. The molecular basis for this predisposition, however, is currently unknown. Brain derived neurotrophic factor (BDNF) is one molecular candidate that may explain pre-existing differences in IL physiology. Polymorphisms in the BDNF gene have been linked to depression and anxiety, which are present in PTSD. BDNF also facilitates NMDA receptor function, and blocking NMDA receptors in prefrontal cortex is sufficient to produce the PTSD phenotype in our rat model. Using BDNF to enhance NMDA currents and downstream signaling may be a means of pharmacologically preventing the PTSD phenotype. We propose the following aims: 1) Determine if baseline (pre-conditioning) busting rates in IL correlate with the degree of extinction success, 2) Determine if baseline bursting in IL is correlated with BDNF protein expression and NMDA receptor phosphorylation, and 3) Attempt to reduce the occurrence of the PTSD phenotype in a normal population of rats by administering BDNF directly into IL or BLA. The findings from this study could explain why a minority of individuals are less resilient in the face of trauma, and could point towards new treatments for preventing the development of PTSD. ? ? ?
| Peters, Jamie; Dieppa-Perea, Laura M; Melendez, Loyda M et al. (2010) Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328:1288-90 |
| Peters, Jamie; Kalivas, Peter W; Quirk, Gregory J (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279-88 |
