The main finding of the current study was that HFS of the IL following retrieval of a conditioned fear memory led to significant reductions in fear during extinction. Another novel finding was that the same effect of IL-HFS was produced in a CTA paradigm. In both paradigms, IL-HFS applied three hours after retrieval did not affect extinction.
Previous studies have shown that microstimulation of IL immediately (i.e., 100–400 msec) after CS presentation decreases the expression of conditioned fear during extinction training and enhances long-term extinction memory 
. Current findings extend these data by demonstrating that HFS of the IL after a 5xCS fear retrieval session is sufficient to reduce fear, and CTA, during extinction training beginning one day after stimulation. Thus, IL stimulation produced significant and lasting reductions in learned fear and aversions even without tight temporal coupling of the CS and the stimulation. These effects were specific to immediate post-retrieval HFS, as the same stimulation protocol applied either three hours after retrieval or prior to conditioning did not affect fear acquisition or fear during subsequent extinction. The lack of changes in fear acquisition is consistent with the inability of IL/mPFC lesions to alter fear learning or expression 
, while the absence of effects of delayed stimulation indicates a critical temporal window for HFS application. This latter finding is consistent with previous work showing that the microinfusion of anisomycin, the protein synthesis inhibitor, into the mPFC three hrs post retrieval did not affect reconsolidation of object recognition 
One possible account of the observed pattern of effects is that HFS applied immediately after retrieval disrupted reconsolidation of the original fear/CTA memory, similar to the effects of protein synthesis inhibitors 
, leading to partial erasure of the original memory. However, this is perhaps a less parsimonious explanation than a decrease in fear/CTA produced by a strengthening of an IL-mediated inhibitory fear memory, for a number of reasons. First are the aforementioned studies demonstrating that IL stimulation facilitates extinction, as well as the wider literature on IL-mediated suppression of conditioned fear via connections to the amygdala (see below). Second, the original fear memory was very readily reinstated in a manner that suggested weakening of an inhibitory memory (following HFS facilitation of extinction) rather than generation of a fear memory de novo (after erasure of an old memory via disruption of reconsolidation). Third, the relatively long retrieval procedure employed in the fear conditioning experiments, comprised of five CS presentations, likely favors extinction over reactivation, suggesting that post-retrieval HFS may have facilitated consolidation of a partial extinction memory. Indeed, microinfusion of a protein synthesis inhibitor into IL disrupts consolidation of both fear extinction 
and CTA extinction following the same behavioral protocol 
It should be noted, however, that the kinetics of extinction following reconditioning were different in the CTA as compared to the fear conditioning paradigm. Notably, while in the fear conditioning paradigm, animals readily show a good ability to re-extinguish, in the CTA paradigm both sham and HFS groups seem to have resistance to extinction following reconditioning. It was previously shown that extinction is slower following double training in CTA 
. Regardless, in both paradigms the return of fear suggests that the original memory was not abolished.
Notwithstanding these issues, an effect of HFS on reconsolidation cannot be fully discounted from the current data. Indeed, this would be a worthy direction in and of itself given recent interest in the therapeutic potential of manipulations affecting reconsolidation 
. In fact, if indeed the effects we observed do occur through disruption of reconsolidation, then they would be the first demonstration that IL stimulation can bolster this effect. This suggests that appropriately timed stimulation of an input to a structure in which reconsolidation is occurring can also disrupt reconsolidation.
An important avenue for future work will be elucidating the mechanisms underlying HFS-induced reductions in fear. In this context, HFS has been found to induce NMDA receptor-mediated long-term potentiation (LTP) in the mPFC 
, and we recently found that fear extinction is accompanied by potentiation and LTP-like excitatory plasticity in mPFC 
. Additionally, fear extinction has been shown to be dependent upon activation of mPFC NMDA receptors 
and correlates with NMDA-mediated mPFC neuronal bursting 
. Together, these findings suggest that the induction of NMDA-mediated LTP could be a substrate for the fear inhibitory effects of IL-HFS, which results in facilitation of extinction. Extinction consolidation is associated with strong activation of c-Fos in the mPFC 
and resistance to extinction is associated with impaired IEG induction in the mPFC 
. Given the role of NMDA receptors in controlling immediate early gene (IEG) transcription, these findings suggest that activation of NMDA-mediated processes may be the primary cause of such IEG activation 
. Furthermore, and in support of the link between changes in plasticity in the IL and facilitation of extinction, it was previously shown that induction of long-term depression in the mPFC is predictive of spontaneous recovery of conditioned fear and resistance to extinction 
and these are associated with failure in IEG induction in the mPFC 
A corollary question is how HFS-driven plasticity changes in IL modify the broader corticolimbic circuit mediating fear and extinction. The IL sends projections to the basolateral amygdala, as well as intercalated cell masses that provide feedforward inhibition of the central amygdala 
. This latter projection has been posited to be a pathway for the IL to inhibit fear responses by suppressing amygdala output 
, and provides a plausible mechanism by which HFS potentiation of IL activity could reduce fear. We propose that the facilitation of extinction is produced following the application of HFS to the IL which seemingly induces an NMDA-dependent potentiation that results in a powerful inhibition of the amygdala by the IL.
In summary, the current study provides novel evidence that HFS of the rat IL after retrieval of either a fear or CTA memory leads to lasting reductions in fear and aversion responses during extinction. These findings are novel as they provide a new tool to ameliorate extinction impairments of aversive memories, and could have implications for understanding mPFC dysfunction in neuropsychiatric disorders characterized by pervasive learned fear, such as PTSD and phobias, and possibly open up novel therapeutic options for these disorders.