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  • Substantial research in animals and humans has characterized

    2018-11-09

    Substantial research in animals and humans has characterized the neural mechanisms underlying fear acquisition and fear extinction learning (Fig. 1). The amygdala, a structure in the medial temporal lobe, is functionally segregated into subnuclei that play distinct roles in fear acquisition and expression (LeDoux, 2007). During fear learning sensory thalamic inputs converge on the lateral amygdala (LA) (Quirk et al., 1995; Collins and Pare, 2000) driving fear expression through the central nucleus (CE) of the amygdala downstream toward output systems that mediate autonomic responses (Maren, 2001). Learning has occurred when the conditioned stimulus alone is able to initiate activity in the LA and elicit a fear response, which prior to conditioning would have been elicited only by the unconditioned stimulus. The ventral medial prefrontal cortex (vmPFC) is critical for mediating fear expression and extinction (Quirk and Mueller, 2008; Phelps et al., 2004). Two distinct subregions of the rodent vmPFC, the prelimbic and infralimbic cortices, play specific functional roles in the expression and inhibition of fear, respectively (Santini et al., 2008; Sierra-Mercado et al., 2011; Sotres-Bayon and Quirk, 2010). The prelimbic cortex (PL) has been implicated in the expression of fear via bilateral projections to and from the amygdala (Milad and Quirk, 2012). The PL receives transient inputs signaling the presence of threat from the amygdala and transforms these signals into sustained firing via downward projections to the CE (Sotres-Bayon and Quirk, 2010) and toward output systems that generate fear responses. The infralimbic cortex (IL) plays a contrasting role in the storage and recall of extinction memory (Quirk and Mueller, 2008). The LA and basal nucleus (BA) of the amygdala excite nmda receptor in the IL in response to safety signals (Repa et al., 2001). Cells in the IL then modulate fear expression through projections to inhibitory (intercalated) cells in the amygdala, that in turn block activity in the CE, suppress outputs to downstream targets and blunt fear expression and related autonomic activity (Milad and Quirk, 2012). Thus, the vmPFC does not simply play an inhibitory role in fear regulation but rather regulates low and high fear states through subnetworks defined by bilateral projections between distinct regions of the vmPFC and functionally specific nuclei in the amygdala (Sotres-Bayon and Quirk, 2010). Many studies have shown that fear circuitry is highly conserved across species, suggesting similar neural mechanisms underlie fear learning and extinction in both mice and humans (Soliman et al., 2010; Milad et al., 2007a; Gottfried and Dolan, 2004). Technical limitations make it challenging to precisely delineate regions homologous to rodent infralimbic and prelimbic cortex in the human brain (Milad and Quirk, 2012). However, the dorsal anterior cingulate cortex (dACC) has been associated with expression of conditioned fear in humans and has been proposed as the human homologue of the rodent prelimbic cortex (Milad et al., 2007a). This is supported by fMRI BOLD data that has shown dACC activity increases with expression of conditioned (Milad et al., 2007a) and unconditioned fear (Dunsmoor et al., 2008). Numerous human studies have demonstrated the importance of the vmPFC in fear extinction learning, supporting this region as functionally and structurally homologous to the rodent infralimbic cortex. Functional imaging studies show that increased vmPFC activity is associated with less fear expression during extinction learning (Phelps et al., 2004; Kalisch et al., 2006) and better recall of extinction memory (Milad et al., 2007b). MRI-based volumetric studies show that larger vmPFC volume is associated with greater fear extinction learning (Shin et al., 2006) and better retention of extinction memory (Milad et al., 2005). The hippocampus also plays a significant role in expression of fear memories that go beyond the current review. Studies show that contextual processing of fear memory is mediated through direct projections from the hippocampus to the amygdala and indirectly through projections to the prefrontal cortex (Sotres-Bayon et al., 2012; Phillips and LeDoux, 1992).