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  • br Alcohol and the amygdala br Alcohol and the CRF

    2021-01-18


    Alcohol and the amygdala
    Alcohol and the CRF1 system Given the marked effects of alcohol on inhibitory neurotransmission in the amygdala and the regulation of amygdalar GABAergic activity by CRF and activity at the CRF1 receptor, the CRF system is a logical site for the actions of alcohol in this region. Human studies have indicated a potential link between crhr1 (the human gene for the CRF1 receptor), polymorphisms, and risk for developing AUD (Glaser et al., 2014, Ribbe et al., 2011, Treutlein et al., 2006). Indeed, withdrawal from alcohol is associated with both increases in anxiety-like behavior as well as increases in extracellular CRF concentration in the amygdala (Funk et al., 2006, Merlo Pich et al., 1995, Zorrilla et al., 2001). Chronic models of alcohol exposure have been shown to increase amygdalar CRF and CRF1 receptor expression (Roberto et al., 2010), and sub-chronic alcohol drinking has been shown to alter CRF immunoreactivity and mRNA, respectively, in the CeA of both adult (Lowery-Gionta et al., 2012, Zhou et al., 2013) and adolescent rats (Allen et al., 2011, Karanikas et al., 2013). Recently, the development of more precise pharmacological tools and transgenic mouse lines has facilitated the investigation of the specific role of the CRF1 receptor in the acute and chronic actions of alcohol in the amygdala.
    Fear and the amygdala The amygdala has been recognized as a major regulator of anxiety and fear-related behaviors for many years. Human participants with PTSD have been found to have reductions in amygdala volume compared with healthy controls (Starcevic et al., 2014), and PTSD has been shown to alter functional connectivity both within amygdalar subnuclei and between these regions and the HMP Linker australia (Brown et al., 2014). Similar evidence for dysregulation of cortical connectivity with the amygdala has been demonstrated in generalized anxiety disorder patients (Etkin, Prater, Schatzberg, Menon, & Greicius, 2009). Amygdala hyperexcitability is a particularly consistent feature of anxiety disorders in human functional neuroimaging studies (Shin & Liberzon, 2010). Increases in amygdala activity have also been observed after the presentation of stress or fear-related visual stimuli in social phobia (Stein, Goldin, Sareen, Zorrilla, & Brown, 2002), arachnophobia (Schienle, Schafer, Walter, Stark, & Vaitl, 2005), and PTSD (Liberzon & Sripada, 2008), although results from patients with generalized anxiety disorder have been mixed (Mochcovitch, da Rocha Freire, Garcia, & Nardi, 2014). Animal models of anxiety-like behavior have revealed some of the underlying neurological mechanisms behind the alterations in amygdalar activity seen in human studies. Dysregulation of GABAergic inhibition of the BLA results in hyperexcitability (Muller et al., 2015, Truitt et al., 2009), which has been associated with anxiety in rodent models and humans (Nuss, 2015, Prager et al., 2016, Terburg et al., 2012). Lesions to the CeA prevent the expression of anxiety-related behavior in the elevated plus maze in response to acute stressors (Ventura-Silva et al., 2013). Optogenetic activation of cells projecting from BLA to CeA promotes anxiolysis, and inhibition of these same cells produces anxiogenesis in the open-field and elevated plus maze tasks (Tye et al., 2011). These studies suggest that changes in activity within the CeA contribute to the expression of anxiogenic behaviors. The amygdala also plays a significant role in fear learning. Generally speaking, the LA has been recognized as a site for the acquisition of fear conditioning, whereas the CeA is involved in the expression of fear-related conditioned responses (Maren & Quirk, 2004). Inputs to the LA are thought to strengthen with repeated pairings of the unconditioned stimulus (US) with the conditioned stimulus (CS), and promote recruitment of downstream targets in the CeAM (Blair et al., 2001, Sigurdsson et al., 2007). CeAL neurons exhibit increased firing in response to fear-conditioned stimuli, and activation of these cells triggers freezing behavior in mice (Ciocchi HMP Linker australia et al., 2010). Information related to fear conditioning can relay from the LA to the CeAM via two pathways: an excitatory direct tract from the BLA, or an inhibitory indirect projection from the CeAL to the CeAM (Duvarci & Pare, 2014).