Dysregulation of the HPA axis resulting in alteration to bot

Dysregulation of the HPA axis, resulting in alteration to both baseline and stress-induced glucocorticoid levels (e.g., cortisol and corticosterone), has been implicated in several diseases and psychopathologies, including anxiety (McEwen et al., 2015, 2016; Shin and Liberzon, 2010). For example, baseline levels of cortisol were positively associated with anxiety scores in young (Takahashi et al., 2005), middle aged (Van Eck et al., 1996) and aged (Lenze et al., 2011) adults, and awakening cortisol levels were higher in individuals with anxiety disorders compared to those without (Vreeburg et al., 2010). Moreover, acute and chronic stress can both lead to increased HPA axis activity, resulting in release of glucocorticoid hormones, and an increase in anxiety (Pulopulos et al., 2015; Shin and Liberzon, 2010). These data suggest that elevated baseline and post-stress glucocorticoids are positively related to anxiety. Additionally, anxiety is thought to be at least partially mediated by corticotropin-releasing factor (CRF) binding to CRFR1 in the limbic system, mainly the amygdala (Arborelius et al., 1999; Binder and Nemeroff, 2010; Reul and Holsboer, 2002; Rosen and Schulkin, 1998; Schulkin et al., 2005; Shin and Liberzon, 2010; Zorrilla et al., 2002). CRF primarily binds to one of two receptors, CRFR1 or CRFR2, but has higher affinity for CRFR1 and this receptor predominates in the hypothalamus, amygdala, cerebellum, pituitary and ligand gated channels (Sanders and Nemeroff, 2016). Hypothalamic CRF is important for initiation of the hypothalamic-pituitary-adrenal (HPA) axis, whereas CRF in the limbic system is important for the autonomic (sympathetic nervous system) and behavioral responses to stress, and is involved in fear and anxiety (Arborelius et al., 1999; Heinrichs and Koob, 2004; McEwen et al., 2015; Müller et al., 2003; Perusini and Fanselow, 2015). Hypothalamic and limbic CRF are independently regulated, but HPA axis output can potentiate the effect of limbic CRF as glucocorticoid binding in the amygdala increases CRF concentrations in that area (Binder and Nemeroff, 2010; Rosen and Schulkin, 1998), providing a possible link between elevated circulating glucocorticoids, CRF, and anxiety. Although various manipulation studies in rodents (e.g., knockout of CRFR1, injection of CRF, injection of CRF antagonists) have shown that increased limbic CRF is anxiogenic, and that this response is driven by binding to CRFR1, the correlational data from humans is mixed (Arborelius et al., 1999; Sanders and Nemeroff, 2016). But, recent evidence suggests that CRF-related single nucleotide polymorphisms (SNPs) might be partially responsible for these discrepancies in the human literature and may help to explain risk and resilience (Binder and Nemeroff, 2010; Feder et al., 2009; Gillespie et al., 2009; Rogers et al., 2013; Weber et al., 2016). For example, three SNPs in the CRFR1 gene (rs7209436 C→ T [minor allele]; rs110402, G → A [minor]; and rs242924 G→ T [minor]) have been linked to HPA axis responsiveness (Mahon et al., 2013; Polanczyk et al., 2009; Tyrka et al., 2009), impact of childhood trauma on adult affect (depression; Bradley et al., 2008), and anxiety (Binder and Nemeroff, 2010; Feder et al., 2009). It seems when combined, the 3 minor CRFR1 SNP alleles are associated with decreased HPA axis responsiveness in adults and may be protective from (stress-related) affective disorders. The endocannabinoid (eCB) system is a neuromodulatory network involved in the regulation of several stress-responsive neural circuits and can impact HPA axis activity (Gorzalka et al., 2008; Hill and McEwen, 2010; Hill and Tasker, 2012; McEwen et al., 2015). The two major signaling molecules of the eCB system are N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), which are synthesized post-synaptically (Hillard et al., 2011). Endocannabinoids bind to CB1 and CB2 receptors. CB1 receptors are the most abundant G-protein-coupled receptors in the central nervous system and are found on GABAergic, glutamatergic, serotonergic, noradrenergic, and dopaminergic terminals, but the predominant effects of eCB signaling result from modifying GABA and glutamate release (see Morena et al., 2016). Regulation of eCBs is done primarily via degrading enzymes, namely fatty acid amide hydrolase (FAAH) which metabolizes AEA, and monoacylglyceride (MAG) lipase, which metabolizes 2-AG. Genetic variability in the gene encoding FAAH may impact anxiety. Specifically, a substitution of a proline at amino-acid 129 with a threonine (C385A, rs324420), alters the regulation of FAAH, but not its enzymatic activity, making it more vulnerable to proteolytic degradation (Chiang et al., 2004; Sipe et al., 2002). The AA or AC genotype is associated with decreased FAAH, increased AEA levels, and reduced amygdala activity (increased inhibitory tone) comparison to the CC genotype (Gunduz-Cinar et al., 2013). Thus, CC individuals seem to be at higher risk for anxiety disorders and anxious behavior as compared to A carriers, and this effect has been shown in humans and in a knock-in mouse model (Dincheva et al., 2015; Hariri et al., 2009). Given these findings, FAAH has recently been tagged as a possible therapeutic target for anxiety disorders (Hill et al., 2013a; Patel et al., 2017).