Characterization of the role of the medial prefrontal cortex and the amygdala in fear and anxiety: a focus on bombesin-like peptides and corticotropin-releasing hormone

This dissertation aimed to more fully characterize the involvement of bombesin-like peptides (neuromedin-B [NMB] and gastrin-releasing peptide [GRP]) and corticotropin-releasing hormone (CRH) in fear and anxiety-related processes. To this end, ventricularly injected GRP and antagonists of the NMB receptor decreased fear and/or anxiety across several animal models of behavior. Whereas NMB appeared to be involved in both fear and anxiety-related processes, GRP affected fear-related processes. In order to determine where in the brain these effects might be primarily localized, several neurochemical alterations were assessed in brain areas known to be involved in fear. Endogenous alterations in peptide levels were seen both within the medial prefrontal cortex (mPFC) and amygdala in response to recall of a fear-inducing shock. To explore this finding further, GRP or its receptor antagonist were microinjected into specific nuclei in the aforementioned areas and it was found that GRP consistently reduced fear at these loci, while the receptor antagonist exhibited both agonistic (reduced freezing) effects as well as antagonistic effects (increased freezing). Further, the observed reductions in freezing appeared to be specific to contextual components of conditioned fear, with the exception of drug administration to the infralimbic (IL) cortex within the mPFC, where we saw reduced freezing to a conditioned tone as well. To determine the endogenous release of GRP and CRH in response to conditioned fear, we collected dialysates from the IL of the mPFC and basolateral amygdala (BLA) in response to a previously conditioned tone. GRP and CRH were elevated 24h after fear conditioning at the BLA, an effect that appears to be related to animal's levels of fear. This was not observed at the IL. Finally, we explored whether the mPFC and amygdala communicated with each other via GRP and/or CRH through a GRP-specific pathway(s). We found that there appears to be a functional pathway between the IL cortex and BLA that is specific to GRP but not to CRH, upon manipulation of IL GRP levels. These studies have further characterized the role of BLPs and CRH in conditioned fear, particularly at the level of the mPFC and BLA and have provided a unique and rich foundation for the physiological role of these peptides and future studies to be developed