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memory the following day (Quirk et al. 2000). However, other investigators have failed to
observe this effect (Gewirtz et al. 1997; Farinelli et al. 2006; Garcia et al. 2006). Again,
compensatory mechanisms following lesioning may be a confounding issue, as a number of
investigators have since found that a more transient inactivation of the infralimbic mPFC, by
infusing compounds into the infralimbic mPFC before extinction training, blocks retrieval of
extinction. For example, infusion of the sodium channel blocker tetrodotoxin (TTX)(Sierra-
Mercado et al. 2006), the NMDA receptor antagonist CPP (Burgos-Robles et al. 2007), a
PKA inhibitor, a beta adrenoceptor antagonist (Mueller et al. 2008), the protein synthesis
inhibitor anisomycin (Santini et al. 2004; Mueller et al. 2008), or the transcription inhibitor
actinomycin (Mueller et al. 2008) into the infralimbic mPFC block retrieval of extinction.
Furthermore infusion of a MAP kinase inhibitor (Hugues et al. 2004; Hugues et al. 2006) or
CPP (Burgos-Robles et al. 2007) immediately following acquisition of training also blocked
extinction retrieval the following day. Enhancing metabolism in the infralimbic mPFC
(Gonzalez-Lima and Bruchey 2004), enhancing brain-derived neurotrophic factor (BDNF)
activity (Bredy et al. 2007) or the activity of AMPA receptors (Zushida et al. 2007) augments
consolidation of extinction. Finally, an increase in the expression of c-fos, an immediate early
gene implicated in synaptic plasticity, is observed in the mPFC following extinction (Santini
et al. 2004), All of these molecular markers point to a role of synaptic plasticity in the mPFC
in the consolidation of extinction memories.
When animals are re-exposed to a conditioned stimulus on days subsequent to the
acquisition of extinction, they can either exhibit the fear memory or the extinction memory,
which are mediated by distinct neural substrates (Bouton 1993; Rescorla 2001; Garcia 2002).
A large body of evidence indicates a role for the mPFC in the retrieval of the extinction
memory. Firstly, an increase in evoked potentials in the mPFC (Herry and Garcia 2002;
Farinelli et al. 2006; Hugues and Garcia 2007), and the degree of synaptic potentiation
displayed by neurons in the mPFC following extinction training, has been shown to correlate
with the degree of extinction memory exhibited (Herry and Garcia 2002; Barrett et al. 2003).
Similarly, high frequency firing of mPFC neurons correlates with the degree of extinction
(Milad and Quirk 2002), and predicts retrieval of the fear memory after extinction training the
following day (Burgos-Robles et al. 2007). In contrast synaptic depression in the mPFC is
associated with expression of the fear memory (Herry and Garcia 2002; 2003). Secondly,
lesioning the infralimbic mPFC results in only the fear memory being exhibited on re-
exposure to the conditioned stimulus (Quirk et al. 2000). Thirdly, enhancing activity in the
mPFC, by triggering LTP in the prelimbic mPFC with high frequency stimulation of the
mediodorsal thalamic nucleus (Herry and Garcia 2002) or the hippocampus (Farinelli et al.
2006), or by stimulating the infralimbic mPFC directly (Milad and Quirk 2002; Milad et al.
2004; Vidal-Gonzalez et al. 2006) facilitates extinction expression. Moreover stimulating the
mediodorsal thalamic nucleus with low frequency stimulation to evoke LTD in the prelimbic
mPFC facilitates expression of the fear memory (Herry and Garcia 2002). In contrast with
these findings, it has recently shown that rats show normal expression of extinction of fear
memories with mPFC lesions (Garcia et al. 2006). Again, however, the discrepancy in the
literature lies with studies examining the effects of lesioning, suggesting methodological
issues.
Thus while some groups have found the association between activity and the extinction
memory to occur in the prelimbic mPFC (Herry and Garcia 2002; Farinelli et al. 2006;
Hugues and Garcia 2007), others have attributed this function only to the infralimbic mPFC
