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  • According to Graeff Graeff innate fear is mediated


    According to Graeff (Graeff, 1990), innate fear is mediated by neural circuitry that consists of at least the amygdala, medial hypothalamus and periaqueductal grey matter. In particular, the BLA has been considered to be a structure closely related to emotional responses to fear, stress and anxiety and may be responsible for the perception of aversive stimuli (Sajdyk and Shekhar, 1997a, Sajdyk and Shekhar, 1997b, Sanders and Shekhar, 1991). In turn, the CeA is related to afferents to central nervous system components, which are responsible for the autonomic and somatic components that occur in fear-related reactions (Davis, 1998). Generally, the amygdaloid complex contributes to fear and anxiety responses by assigning emotional and motivational significance to sensorial stimuli (Ledoux, 2000). Corticotropin-releasing factor (CRF) is involved in the coordination of autonomic and endocrine responses and behavioral responses to stress (Carrasco and Van De Kar, 2003, Vale et al., 1981). Indeed, the release of CRF and subsequent secretion of N,N-Dimethylsphingosine plays a central role in an organism’s preparation to cope with imminent injuries, particularly when faced with ambiguous cues such as those elicited by aversive environment (Merali et al., 2004). Additionally, it is important to note that CRF has an essential role in the fight or flight responses, increases heart rate and glucocorticoid levels, inhibits digestive function (Dunn and Berridge, 1990) and still leads to anxiety (Takahashi et al., 1989). The effects of CRF are mediated by coupling to CRF1 and CRF2 receptors (Hauger et al., 2006, Hillhouse and Grammatopoulos, 2006). In particular, CRF1 receptors can be found in several brain areas including pituitary, brain stem, cerebellum, amygdala, and cortex. CRF2 receptors have a similar distribution pattern in the reshus monkey brain with the exception of increased densities in the brain regions including the neocortex, amygdala and hippocampal formation (Sánchez et al., 1999). Additionally, while the activation of CRF1 receptors has been related to increased reactions to stress and anxiety (Fekete and Zorrilla, 2007), the involvement of CRF2 and the relationship between CRF1 and CRF2 in emotional modulation have not been fully clarified (Zorrilla et al., 2013). From this perspective, the present study indicates that blocking either CRF1 or CRF2 in the BLA and CeA had a similar effect on fear and anxiety modulation because the administration of CP-376395 (the CRF1 receptor antagonist) or Astressin 2B (the CRF2 receptor antagonist) in these areas promoted a reduction of the TI response, an innate fear behavior. So, we hypothesize that both CRF receptors, CRF1 and CRF2, are activated by endogenous CRF, which is released during TI behavior. Taking into account that TI response is considered a last resort aimed at the survival of the animal (Gallup, 1977, Klemm, 1971) the combined action of CRF1 and CRF2 receptors can be crucial for emission of the appropriate defensive response. Indeed, CRF1 and CRF2 share functions in emotional responses, and inhibition of both receptors promotes a stronger decrease in stress-induced behavior than inhibition of either receptor alone (Takahashi, 2001). Moreover, the combined action of CRF1 and CRF2 has been suggested since the emotional behavior can be mediated by CRF1 receptor activation and modulated by CRF2 receptors (Cook, 2004, Reul and Holsboer, 2002).