Hippocampal–Prefrontal BDNF and Memory for Fear Extinction

Abstract

Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.

Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

“…Our results indicate a similar requirement of the IL in the consolidation of recent and remote fear extinction and join the recent findings reported by Rosas-Vidal et al (2014) who showed similar effect of intra-IL microinfusion of brainderived neurotrophic factor (BDNF) in recent (1 day after conditioning) and remote (14 days after conditioning) extinction of fear memories. This corroborates previous results that we and others obtained regarding the crucial role of the IL subregion of the mPFC in the mediation of consolidation of recent fear extinction (Milad et al, 2004;Kritman and Maroun, 2012;Laurent and Westbrook, 2009;Sierra-Mercado et al, 2010) and extends it to remote fear memory.…”

“…Using either reversible inactivation or protein synthesis inhibitor targeting the postretrieval consolidation phase (Akirav et al, 2006a;Eisenberg et al, 2003), we showed that the IL is involved in extinction consolidation of both recent and remote CFC as was recently shown (Rosas-Vidal et al, 2014). Targeting the same time window, the results show that the IL is involved only in extinction consolidation of recent, but not remote, COA.…”

“…Although previous studies indicated that remote fear extinction can affect activation and lead to structural changes in the IL (Vetere, et al, 2011;Vetere, et al, 2012), there was neither direct assessment for the role of the IL in extinction of remote memories nor direct comparison of the IL involvement in recent and remote fear extinction. Our results suggest a permanent role of the IL in the consolidation of fear extinction that is not limited to the age of the memory (see also Rosas-Vidal et al, 2014). It should be noted however that there is a difference between the kinetics of fear extinction in the treated groups in recent as compared with remote fear extinction.…”

“…It is important to note that standard theory of systems memory consolidation postulates that the hippocampus has a time-limited role in the storage of memories, with a more important role of the mPFC in remote memories as was shown for CFC (Frankland and Bontempi, 2005;Knowlton and Fanselow, 1998;Squire and Alvarez, 1995). Even if recent evidence indicates that IL is similarly involved in extinction consolidation of both recent (1 day) and remote (14 days) fear memories (Rosas-Vidal et al, 2014), a hippocampaldependent memory task (Goshen et al, 2011;Zelikowsky et al, 2012), no study has yet investigated and compared the role played by the IL in extinction of recent and remote memory in conditioned food aversion, a nonfear-based association considered as a hippocampal-independent memory task (Ballarini et al, 2009;Cui et al, 2005;Ding et al, 2008;Josselyn et al, 2004). For this purpose, we used conditioned odor aversion (COA) that relies on the association between tasteless odorized water and malaise feeling that creates robust memory that we have previously shown to last for weeks (Chapuis et al, 2007;Desgranges et al, 2009;Sevelinges et al, 2009a, b).…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…Although studies of the effectiveness of therapeutics have generally used SEFL models other than restraint, a recent study showed that 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, was able to rescue impaired extinction following restraint stress (Andero et al 2011). TrkB is a receptor for brain-derived neurotropic factor (BDNF), a regulator of neuronal plasticity that supports cognition and learning throughout life (Bramham and Panja 2014;Karpova 2014;Lu et al 2014) and can accelerate extinction in classical fear learning paradigms (Peters et al 2010;Rosas-Vidal et al 2014). The efficacy of this approach is likely to be tested in human studies because 7,8-DHF is safe and can cross the blood-brain barrier, and evidence supports the hypothesis that BDNF signaling is altered in PTSD patients (Dell'Osso et al 2009;Hauck et al 2010;Soliman et al 2010).…”