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  • nigericin australia Within the BLA both CRF


    Within the BLA, both CRF and the CRF1 receptor have been shown to functionally regulate synaptic activity. In vivo, CRF release into the BLA originates from projections from the CeA (Roozendaal, Brunson, Holloway, McGaugh, & Baram, 2002). Central administration of both CRF and CRF1 agonists has been shown to activate the BLA and produce anxiogenic behavioral responses (Dube et al., 2000, Rainnie et al., 2004). Exogenous application of CRF peptide in BLA slices likewise increased the excitability of neurons (Ugolini, Sokal, Arban, & Large, 2008), an effect which was diminished following chronic unpredictable stress and shown to be mediated via the CRF1 receptor (Sandi et al., 2008). Microinjection of CRF specifically within the BLA activated CaMKII-containing projection neurons but not GAD-containing interneurons (Rostkowski, Leitermann, & Urban, 2013). Chronic administration of the CRF1 and CRF2 agonist urocortin produced long-lasting anxiety responses that required NMDA receptor and CaMKII activation and produced hyperexcitability of the BLA network due to reduced local inhibition (Rainnie et al., 2004, Sajdyk et al., 1999). Together, these findings indicate a general enhancement of excitatory synaptic transmission in the BLA following acute in vivo and ex vivo application of CRF that is blunted by chronic stress and chronic CRF activation. The CRF system also plays an important role in the regulation of synaptic transmission in the central amygdala. Although the CeA receives input from CRF+ projections originating in the paraventricular hypothalamus (Hernández et al., 2015) and the bed nucleus of the stria terminalis (Gungor, Yamamoto, & Pare, 2015), CRF function in the CeA is also driven by local microcircuitry (Sanford et al., nigericin australia 2017). CRF and GABA are co-localized within the CeA (Day, Curran, Watson, & Akil, 1999), and CRF has been to shown to regulate GABAergic neurotransmission in this nigericin australia region. Exogenous application of CRF to CeA slices increases presynaptic GABA release in a CRF1, but not CRF2, -dependent manner (Kang-Park et al., 2015, Nie et al., 2004, Roberto et al., 2010). The effects of CRF on inhibitory neurotransmission in the CeA are regulated in part by protein kinase C-epsilon (PKCε); PKCε knockout mice exhibited increased baseline GABAergic tone in the CeA but were not responsive to the acute effects of exogenous CRF application, and PKCε inhibition occluded the effects of acute CRF in wild-type mice (Bajo et al., 2008, Blasio et al., 2018). CRF has also been shown to alter excitatory transmission within the CeA. CRF application reduced evoked glutamate responses and enhanced glutamate release in the CeA of Sprague-Dawley rats (Liu et al., 2004, Varodayan et al., 2017) and C57BL/6 mice (Silberman, Matthews, & Winder, 2013). In Wistar rats, CRF application had divergent effects on glutamatergic signaling, with a subset of CeA neurons exhibiting enhanced glutamate release following exogenous CRF application and a subset exhibiting reductions in glutamate release (Herman, Varodayan, et al., 2016). Previous limitations in identifying and targeting CRF1 neurons in the amygdala were overcome by the development of a BAC transgenic mouse line expressing green fluorescent protein (GFP) in CRF1-containing neurons (Justice, Yuan, Sawchenko, & Vale, 2008). Immunohistochemical examination of GFP expression in the amygdala complex in this mouse indicates that CRF1 neurons compose discrete cell populations with restricted expression in discrete amygdala subnuclei (Fig. 1A). Earlier work by our group utilized this transgenic mouse model approach to examine inhibitory transmission in CRF1-containing (CRF1+) and unlabeled (CRF1−) neurons in the CeA. We validated this model to establish that GFP expression was a reliable indicator of CRF1+ neurons in the amygdala and found that CRF1+ and CRF1− neurons exhibited distinct inhibitory characteristics. CRF1+ CeA neurons exhibited a significant ongoing tonic conductance mediated by GABAA receptors containing the α1 subunit. In contrast, unlabeled (CRF1−) CeA neurons possessed the potential for a tonic conductance mediated by δ subunit-containing GABAA receptors (Herman, Contet, et al., 2013). Paired recordings demonstrated that CRF1− neurons form local inhibitory synapses onto CRF1+ neurons, a portion of which project out of the CeA into the bed nucleus of the stria terminalis (Herman, Contet, & Roberto, 2016). The specific role of CRF1+ and CRF1− cells in the CeA suggests that CRF1+ neurons may make up distinct neuronal populations in other amygdala nuclei, including the BLA, and that CRF1 neurons may display distinct patterns of inter- and intra-amygdalar connectivity (Fig. 1B).