The central amygdala corticotropin releasing factor system regulates anxiety-like behavior in an age- and sex- dependent manner in rats

The corticotropin releasing factor (CRF) system is a key regulator of anxiety-like behavior and a major contributor to addiction. The canonical anxiogenic role of CRF has been largely based on CRF manipulations in adult male rodents, particularly within the central amygdala (CeA), despite evidence that underlying neurobiological mechanisms of anxiety are sex- and age-dependent. Our lab has shown that the physiological response to CRF receptor 1 (CRFR1) activation within the medial CeA, a brain region associated with anxiety and addiction, varies with both age and sex. Therefore, in the current study, we investigated the effects of CRFR1 activation in the CeA on anxiety-like behavior in naïve juvenile (∼postnatal day [P] 25), adolescent (∼P45), or adult (∼P80) male and female Sprague Dawley rats. Rats were given bilateral cannula in the CeA and then tested in the light-dark box test following an infusion of either the CRFR1 agonist Stressin-1 (1 µM) or vehicle. In contrast to the previously established anxiogenic effects of CRF agonists, we found that intra-CeA Stressin-1 decreased anxiety-like behavior in females regardless of age and juvenile males, with no significant effects evident in adolescent or adult males. Notably, RNAscope in situ hybridization revealed no differences in CRFR1 or CRF mRNA across age or sex. Taken together, these findings further highlight the importance of age and sex on CRF system regulation of anxiety-like behavior, providing a background for the development of more targeted treatments of anxiety disorders and addiction.