Together these studies demonstrate that

Together these studies demonstrate that while the amygdala plays a role in acquisition, storage and retrieval of fear memory, regulation of fear is dependent on bilateral connections between the amygdala and the vmPFC. Converging evidence has linked anxiety and anxiety-related disorder to impaired fronto-amygdala regulation. Trait anxiety has been associated with heightened amygdala activity during fear learning in human adults (Indovina et al., 2011), while individuals with increased trait anxiety show compromised fear extinction learning that appears to be driven by dysreguated interactions between frontal and amygdala regions (Indovina et al., 2011; Lissek et al., 2005). In clinical populations, PTSD patients have shown diminished prefrontal blood flow in PET studies (Bremner et al., 1999; Semple et al., 1996), reduced vmPFC activity when recalling traumatic events (Shin et al., 1999) and impaired fear extinction learning (Milad et al., 2008). In sum, these data suggest diminished functional capacity in fronto-amygdala circuitry may underlie deficits in fear extinction learning and could be a factor contributing to the onset of pathological fear and anxiety. Anxiety disorders peak during adolescence (Merikangas et al., 2010; Costello et al., 2005). These disorders often persist into adulthood and early onset is often predictive of the most severe and disabling forms of adult psychopathology (Andersen and Teicher, 2008; Kim-Cohen et al., 2003). Adolescence is also a developmental stage during which functional immaturity of fronto-amygdala circuitry is observed with stronger connectivity between early-developing subcortical regions than in later-maturing prefrontal regions (Casey et al., 2008). Therefore, the PFC is less capable of sufficiently suppressing emotions and actions mediated by subcortical limbic structures during adolescence. In the next section, we review studies that collectively describe how functional immaturity in prefrontal-amygdala connections may underlie adolescent-specific diminished fear extinction learning.
Development of fear extinction learning: structural and functional changes during adolescence There are regional structural and functional changes in EZ Cap Reagent GG circuitry during adolescence. Nonhuman animal work and post mortem human studies show that synaptic pruning reaches adult numbers in sensorimotor cortices before the prefrontal regions (Bourgeois et al., 1994, Huttenlocher and Dabholkar, 1997). These regional changes are paralleled by human developmental imaging studies that show peaks in cortical thickness and volume in sensorimotor cortices and subcortical regions before association cortices (Gogtay et al., 2004; Sowell et al., 1999, 2004; Mills et al., 2014). This pattern of development can result in a functional imbalance during adolescence characterized by high, subcortically driven reactivity to emotional events and low capacity to regulate emotional responses to these events through prefrontal mechanisms. Recent evidence (McCallum et al., 2010; Pattwell et al., 2012a; Hare et al., 2008) suggests that immature top down ventromedial (infralimbic) prefrontal projections to the amygdala during adolescence may lead to diminished fear extinction learning (Fig. 1). An example of functionally altered frontolimbic activity during adolescence from our own work examined developmental changes in fMRI BOLD signal to threat-related cues (fearful faces) (Fig. 2A). We demonstrated that adolescents show heightened amygdala activity to threat cues relative to both children and adults (Hare et al., 2008; Fig. 2B). These results are consistent with other work showing that adolescents exhibit greater amygdala responses to emotional pictures than adults (Guyer et al., 2008; Monk et al., 2003). In this study, threat cues generated behavioral inhibition, as measured by increased time to respond to threat relative to non-threat cues. Threat-related slowing in response latencies corresponded to greater amygdala and decreased vmPFC activity (Fig. 2C). This inverse pattern between the vmPFC and amygdala is consistent with the role of the prefrontal cortex in modulating and regulating the fear response via projections to inhibitory cells (intercalated cells) in the amygdala that in turn inhibit central nucleus output that dampens the fear response. To further constrain the interpretation of our findings we examined changes in amygdala activity as a function of time and to what extent habituation of the amygdala response over time was correlated with vmPFC activity. Greater habituation in the amygdala was associated with greater connectivity between vmPFC and amygdala, with less habituation in the amygdala response correlating with higher self-reported trait anxiety. These latter findings are consistent with studies showing that fear regulatory circuitry is functionally compromised in anxious individuals (Kim and Whalen, 2009). While this study provides support consistent with our hypothesis of diminished functional capacity of prefrontal regions to inhibit amygdala responses to threat-related cues, there are not as of yet any published studies that have directly tested this idea using associative (Pavlovian) learning paradigms in adolescent humans. For insight, we turn to human behavioral studies and rodent behavioral and neurobiological evidence that suggest adolescent-specific changes in fear regulation are mediated by a functional imbalance between prefrontal inhibitory regions and subcortical activity that drives fear expression.