Dissociable Roles of Prelimbic and Infralimbic Cortices, Ventral Hippocampus, and Basolateral Amygdala in the Expression and Extinction of Conditioned Fear

Abstract

Current models of conditioned fear expression and extinction involve the basolateral amygdala (BLA), ventral medial prefrontal cortex (vmPFC), and the hippocampus (HPC). There is some disagreement with respect to the specific roles of these structures, perhaps due to subregional differences within each area. For example, growing evidence suggests that infralimbic (IL) and prelimbic (PL) subregions of vmPFC have opposite influences on fear expression. Moreover, it is the ventral HPC (vHPC), rather than the dorsal HPC, that projects to vmPFC and BLA. To help determine regional specificity, we used small doses of the GABAA agonist muscimol to selectively inactivate IL, PL, BLA, or vHPC in an auditory fear conditioning and extinction paradigm. Infusions were performed prior to extinction training, allowing us to assess the effects on both fear expression and subsequent extinction memory. Inactivation of IL had no effect on fear expression, but impaired the within-session acquisition of extinction as well as extinction memory. In contrast, inactivation of PL impaired fear expression, but had no effect on extinction memory. Inactivation of the BLA or vHPC impaired both fear expression and extinction memory. Post-extinction inactivations had no effect in any structure. We suggest a model in which amygdala-dependent fear expression is modulated by inputs from PL and vHPC, whereas extinction memory requires extinction-induced plasticity in IL, BLA and/or vHPC.

Learned together, extinguished apart: reducing fear to complex stimuli

“…Recalling a cue that was previously extinguished has been shown to activate the IL but not the PrL, suggesting that the IL plays a role in inhibiting the fear response after extinction training (Milad and Quirk 2002;Santini et al 2008). In this experiment, the increased activity seen in the IL after retrieval of the light is consistent with the low levels of freezing induced by the light portion of the compound and could be the result of engaging a mechanism similar to extinction (Milad and Quirk 2002;Mueller et al 2008;Sierra-Mercado et al 2011) or fear inhibition (Vidal-Gonzalez et al 2006;Laurent and Westbrook 2009). Additionally, c-Fos expression in the dorsal CA1 subfield of the hippocampus, a region known to play an important role in the retrieval of contextual fear memories (Hall et al 2001;Strekalova et al 2003;Lee and Kesner 2004;Hunsaker and Kesner 2008) shows that both retrieval of the light and T+L leads to increased activation.…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Anxiolytic effects of CBD in the EPM and VCT occurred upon microinjection into the BNST, where they depended on 5-HT 1A R activation [79], and also upon microinjection into the central nucleus of the amygdala [78]. In the prelimbic cortex, which drives expression of fear responses via connections with the amygdala [94], CBD had more complex effects: in unstressed rats, CBD was anxiogenic in the EPM, partially via 5-HT 1A R receptor activation; however, following acute restraint stress, CBD was anxiolytic [87]. Finally, the anxiolytic effects of systemic CBD partially depended on GABA A receptor activation in the EPM model but not in the VCT model [61,62].…”

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

“…Activation of these cells via increased firing in IL inhibits the LA signals to the CE, decreasing the expression of conditioned fear responses (Berretta, 2005;Likhtik et al, 2008). In contrast to the IL, the neighboring PL opposes extinction recall, driving the expression of fear responses (Corcoran and Quirk, 2007;Sierra-Mercado et al, 2011;Sotres-Bayon et al, 2012). During extinction training, CSevoked activity within PL predicts the subsequent failure of extinction retrieval (Burgos-Robles et al, 2009), suggesting that the dynamic interaction between the amygdala and IL and PL cortical regions determines the success or failure of extinction learning.…”