br Amygdala microcircuitry and fear learning Recent work

Amygdala microcircuitry and fear learning Recent work has begun to dissect functional amygdala circuits that are responsible for the acquisition and expression of fear learning. Ciocchi et al. (2010) identified separable populations of potassium channel within the CeAL that have opposite responses to CS presentation, those that increase firing in response to the CS (CElon cells), and those that decrease firing in response to the CS (CEloff cells). In a related paper, Haubensak et al. (2010) demonstrated that the CEloff population is likely PKCδ-containing neurons that send a GABAergic inhibitory projection to the CeAM, regulating CeAM activity and thereby altering the expression of conditioned fear. Both studies also provided evidence of reciprocal inhibition of CElon and CEloff cells within the CeAL. Consistent with these findings, genetic silencing of PKCδ-containing cells increased freezing behavior in a subset of conditioned animals. Together, these results identified an inhibitory microcircuit within the CeAL that functionally regulates CeAM activity and may in turn alter the expression of conditioned fear. Subsequently, Li et al. (2013) demonstrated plasticity of glutamatergic signaling onto the somatostatin-positive (SOM+) GABAergic cells of the CeAL. This population is distinct from the PKCδ+ neurons characterized by Ciocchi et al. (2010) and Haubensak et al. (2010) and does not project to the CeAM; rather, these cells form local inhibitory microcircuits that gate activity of the CeAL. Stimulation of this SOM+ cell population triggered freezing behavior in naïve mice, and inhibition of this population reduced the expression of conditioned fear. Additional populations of SOM+ cells in the CeAL project to the periaqueductal gray and paraventricular nucleus of the hypothalamus, where they regulate freezing behavior (Penzo, Robert, & Li, 2014). More recent work from this group has demonstrated that SOM+ CeAL cells activate in real-time in response to external threats; activation of this population is associated with more passive defensive strategies such as freezing, whereas inhibition of this population promotes active avoidance behaviors (Yu, Garcia da Silva, Albeanu, & Li, 2016). As a whole, these studies suggest that following fear conditioning, the LA can relay information to the CeAL, where activation of PKCδ+ cells that project to the CeAM triggers the expression of conditioned fear responses, and conversely activation of the local SOM+ CeAL cells inhibits PKCδ+ cells, reducing the expression of conditioned fear responses. However, the added complexity of local versus projection SOM+ neurons exerting opposite effects on freezing behavior, and recent reports of significant overlap at the level of mRNA between cell markers in the CeAL (McCullough, Morrison, Hartmann, Carlezon, & Ressler, 2018), highlight the need for further characterization of specific cell populations recruited during fear-related behavioral tasks and the functional role of these circuits in the cellular and behavioral output of the amygdala as a whole.
CRF involvement in fear/anxiety Given the ability of CRF and CRF1+ cells to regulate BLA and CeA neuronal activity, it is unsurprising that the CRF system has also been shown to regulate fear and anxiety-like behaviors. Acute stress enhances CRF release in the amygdala (Koob & Heinrichs, 1999), and the systemic administration of CRF increases anxiety-like behavior in rodent models, including acoustic startle, elevated plus maze, forced swim test, and defensive withdrawal in an open field (see Dunn & Berridge, 1990 for review). Restraint stress has also been shown to increase CRF1 receptor mRNA in the CeA and BLA of Wistar rats (Ciccocioppo et al., 2014). CRF1 agonists generally produce pro-stress behavioral effects, whereas CRF1 antagonists generally produce anxiolysis in behavioral tests of stress responsivity (for review, see Koob, 2010). The Marchigian Sardinian P (msP) rat strain exhibits increased anxiety-like behaviors accompanied by constitutive increases in CRF1 expression within the CeA (Cippitelli et al., 2015, Natividad et al., 2017). CRF activity within the CeA has also been shown to functionally regulate anxiety-like behavior (Rassnick, Heinrichs, Britton, & Koob, 1993). In the laterocapsular division of the CeA, CRF peptide and the CRF1 receptor have also been shown to play a role in nociception (Ji et al., 2013, Ji and Neugebauer, 2008), cellular adaptations to chronic pain (Fu and Neugebauer, 2008, Ji and Neugebauer, 2007), and the expression of pain-related anxiety behaviors (Ji, Fu, Ruppert, & Neugebauer, 2007).