Brain-derived neurotrophic factor (BDNF) acting through the tyrosine kinase B receptor (TrkB) is thought to be a critical mediator of learning. As there are no available selective antagonists of TrkB, we used a lentivirus encoding a dominant-negative TrkB (TrkB.t1) to antagonize BDNF signaling during extinction of conditioned fear. Whereas TrkB.t1-infected rats showed normal within-session extinction, their retention of extinction was impaired, suggesting that amygdala TrkB activation is required for the consolidation of stable extinction memories.The persistence of fear memories is thought to be a major contributor to the morbidity associated with a number of psychiatric disorders, including post-traumatic stress disorder, panic disorder, and specific and social phobia 1 . Although currently available anxiolytic medication can be helpful in decreasing symptoms, the most effective means of specific treatment for these disorders includes exposure-based psychotherapy that targets the specific fear. This form of treatment relies on the underlying process of extinction of fear. Our group has recently had success in using agents that augment extinction in rodent models to successfully enhance the treatment of specific phobias in humans 2 . By understanding the mechanisms of encoding and consolidation of extinction, new and powerful treatment modalities may become available.The extinction of fear involves new learning of an inhibitory signal that competes with the previously learned fear memory. Extinction is dependent upon the basolateral nucleus of the amygdala (BLA) 3,4 and the infralimbic cortex 5,6 . Within the BLA, it is probably dependent on the NMDA receptor 3,4 and on voltage-gated calcium channels (VGCCs) 7 . Notably, recent evidence suggests that the extinction of fear and the extinction of drug use may involve similar mechanisms within the BLA (ref. 8). However, despite a wealth of behavioral data, there is limited understanding of the molecular mechanisms mediating the acquisition and consolidation of extinction learning.Correspondence should be addressed to K.J.R. (kressle@emory.edu).. Publisher's Disclaimer: This PDF receipt will only be used as the basis for generating PubMed Central (PMC) documents. PMC documents will be made available for review after conversion (approx. 2−3 weeks time). Any corrections that need to be made will be done at that time. No materials will be released to PMC without the approval of an author. Only the PMC documents will appear on PubMed Central --this PDF Receipt will not appear on PubMed Central.Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. BDNF acting on the TrkB receptor within the amygdala is required for normal learning of conditioned fear 9 . To examine its role in extinction, we first examined whether expression of the gene encoding BDNF is altered following the extinction of conditioned fear. Rats were fear-conditioned with 2...

We examined brain-derived neurotrophic factor (BDNF) mRNA expression across the olfactory system following fear conditioning. Mice received 10 pairings of odor with footshock or equivalent unpaired odors and shocks. We found increased BDNF mRNA in animals receiving paired footshocks in the multiple regions examined including the posterior piriform cortex (PPC) and basolateral amygdala (BLA). This was in contrast to the unpaired and odor-alone treatments, where BDNF mRNA was increased in the olfactory bulb (OB) and anterior piriform cortex (APC) only, but not the higher olfactory areas. We propose that odor exposure increases expression of BDNF in the OB and APC while the PPC and BLA increase BDNF mRNA only when associative learning occurs.Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has been shown to play a role in learning and memory (Tyler et al. 2002;Rattiner et al. 2005). Besides its neurotrophic activity, BDNF, working through its primary receptor TrkB, is involved in a number of downstream effects related to learning including long-term synaptic plasticity (Lohof et al. 1993;Korte et al. 1995), morphological changes in dendritic spines (Tyler and Pozzo-Miller 2003;Rex et al. 2007), gene transcription via CREB (Minichiello et al. 2002), and the recruitment of PSD-95 to the synapse (Yoshii and Constantine-Paton 2007).In the hippocampus, BDNF mRNA increases with hippocampal-dependent tasks such as the Morris Water Maze (Falkenberg et al. 1992) and contextual learning (Hall et al. 2000;Mizuno et al. 2000). Locally blocking the action of BDNF prevents learning in hippocampal-dependent tasks as shown by infusion of antisense BDNF oligonucleotides (Mizuno et al. 2000) and by regional knock-out of BDNF (Heldt et al. 2007). In the amygdala, expression of a truncated form of the TrkB receptor, which blocks the activity of the full-length receptor, blocks both the acquisition of a cued fear (Rattiner et al. 2004b) and extinction of fear (Chhatwal et al. 2006).Although many studies of BDNF in sensory systems have focused on its developmental role, few studies have linked BDNF to learning in the olfactory system, even though the olfactory system at multiple levels shows signs of learning-induced change, including LTP (Ennis et al. 1998;Lebel et al. 2001), dendritic spine plasticity (Knafo et al. 2001), and c-fos activation (Funk and Amir 2000;Schettino and Otto 2001;Illig 2007). In the olfactory system, BDNF is expressed in the olfactory bulb and piriform cortex, and is upregulated in these areas following kainic acid-induced seizures (Katoh-Semba et al. 1999). In slice preparations of the main olfactory bulb, BDNF has been shown to cause an increase in dendritic spines in granule cells (Berghuis et al. 2006). In the piriform cortex, deficits in BDNF have been linked to a decrease in dendritic spine number (Nanobashvili et al. 2005). BDNF is also essential to the differentiation of regenerating cells within the olfactory bulb (Benraiss et al. 2001).No study has yet investigated a...