Inhibition of corticotropin releasing factor expression in the central nucleus of the amygdala attenuates stress-induced behavioral and endocrine responses

Abstract

Corticotropin releasing factor (CRF) is a primary mediator of endocrine, autonomic and behavioral stress responses. Studies in both humans and animal models have implicated CRF in a wide-variety of psychiatric conditions including anxiety disorders such as post-traumatic stress disorder (PTSD), depression, sleep disorders and addiction among others. The central nucleus of the amygdala (CeA), a key limbic structure with one of the highest concentrations of CRF-producing cells outside of the hypothalamus, has been implicated in anxiety-like behavior and a number of stress-induced disorders. This study investigated the specific role of CRF in the CeA on both endocrine and behavioral responses to stress. We used RNA Interference (RNAi) techniques to locally and specifically knockdown CRF expression in CeA. Behavior was assessed using the elevated plus maze (EPM) and open field test (OF). Knocking down CRF expression in the CeA had no significant effect on measures of anxiety-like behavior in these tests. However, it did have an effect on grooming behavior, a CRF-induced behavior. Prior exposure to a stressor sensitized an amygdalar CRF effect on stress-induced HPA activation. In these stress-challenged animals silencing CRF in the CeA significantly attenuated corticosterone responses to a subsequent behavioral stressor. Thus, it appears that while CRF projecting from the CeA does not play a significant role in the expression stress-induced anxiety-like behaviors on the EPM and OF it does play a critical role in stress-induced HPA activation.

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis

“…In contrast to the effects of CRF manipulation in the BNST on anxiety, disruption of CRF in the CeA has not been shown to affect anxiety behavior (Lee and Davis, 1997; Callahan et al, 2013). One study took advantage of the finding that intracerebroventricular administration of CRF facilitates anxiety and directly tested whether this CRF mediated increase in anxiety can be blocked by NMDA lesions of the CeA or the BNST (Lee and Davis, 1997).…”

“…The authors found that lesions of the BNST blocked CRF enhanced anxiety while CeA lesions had no effect, further demonstrating the important role of CRF in the BNST on anxiety behavior. Another recent study used RNA interference of CRF in the CeA to locally knock down CRF expression and found no effect on anxiety (Callahan et al, 2013). Interestingly, we have also tested the effect of disruption of CRF producing NR1 neurons on anxiety behavior.…”

Central Nervous System Control of Gastrointestinal Motility and Secretion and Modulation of Gastrointestinal Functions

“…In contrast, lesions of the CeA decrease anxiety-like behaviors, decrease CRF mRNA expression and CRF levels within the hypothalamus and decrease the stress-induce release of ACTH and corticosteroids (91, 519); reviewed in (133). Functional magnetic resonance imaging (fMRI) and positron emission tomography techniques have demonstrated that patients exhibiting GI hypersensitivity show altered processing of visceral stimulation and increased activation of several CNS regions including the amygdala (322, 323) while rodent studies have shown an increased neuronal activation in CeA following colorectal distention (283, 533).…”

“…Furthermore, stress-susceptible species of rodents have been found to have increased levels of CRF within the CeA (206, 439) and CeA CRF levels are also increased in animal models of colonic hypersensitivity (199, 380). In addition to increasing anxiety- and stress-related behaviors, microinjection of corticosterone into the amygdala increases CRF levels (485); these actions are also attenuated by CRF antagonists (91). These, and other lines of evidence, have led to the suggestion that the sensitivity of the CeA to corticosterone may underlie the correlation between the stress and GI hypersensitivity observed in many IBS patients [reviewed in (345)].…”

Energy Metabolism and Behavior in the Corticotropin-Releasing Factor Family of Peptides

“…Dabrowska et al (2013) provide evidence that CRF neurons in the BNST and PVN are phenotypically different based upon their physiological response to local neurotransmitter release and whether they also synthesize GABA or glutamate and may have either inhibitory or excitatory actions, respectively. Callahan et al (2013) use RNAi techniques to locally knockdown CRF expression in the central nucleus of the amygdala. Interestingly, disruption of CRF synthesis in this brain area interferes with stress-induced HPA activity and the expression of anxiety-like behaviors during stress.…”