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Roman, Carolyn W.

Neuroscience Graduate Program

2013

Ph. D.

In response to stressor exposure, both central and peripheral systems become engaged to rectify perturbations in homeostasis and allow the organism to react to the threat. The HPA-axis is activated to stimulate glucocorticoid release and the autonomic nervous system triggers the "fight or flight" response through increased adrenal epinephrine release. Hence, these systems are highly adaptive. However, excessive or continuous activation of stress response systems can cause maladaptive molecular changes that can disrupt normal functioning of these circuits and manifest as anxiety disorders. The bed nucleus of the stria terminalis (BNST) is known to be a major relay for signals involved in emotional salience and metabolic homeostasis and its output mediates functioning of downstream endocrine and behavioral stress-responses. Activation of the BNST occurs in response to a number of aversive stressors, especially long-duration psychogenic (psychological) or unpredictable threats. Stress-induced plasticity within the BNST has been implicated in dysregulation of HPA and autonomic responses to stress as well as anxiety-like behavioral responses.
Our laboratory has previously described substantial increases in pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide with neurotransmitter and neurotrophic functions selectively within the BNST following a chronic stress paradigm in rodents. Furthermore, single injections of PACAP into the BNST increased anxietylike behavior and decreased food intake, behavioral consequences that are also observed following exposure to chronic stress. We have now further characterized these stressinduced increases in PACAP expression in specific subregions of the BNST and found robust changes in the oval nucleus of the BNST. Lesions of this subregion or long-term treatment with a PACAP receptor antagonist were subsequently found to prevent or reduce the maladaptive effects of chronic stress exposure. As PACAP binds three separate receptor subtypes, we also investigated which receptor mediates anxiety-related responses.
Our data suggest that stress-related PACAP signaling in the BNST is mediated by PACAP-selective PAC1 receptors and not by the non-selective VPAC receptors. As disruptions in HPA-axis functioning are often observed in patients with affective disorders, we also performed experiments showing that BNST PACAP signaling can activate the HPA-axis. Finally, increased circulating PACAP levels have been associated with PTSD in women; hence, we investigated changes in. circulating PACAP levels in both male and female rats exposed to the chronic variate stress paradigm. Interestingly, we found a significant increase in circulating levels of PACAP in male rats exposed to chronic variate stress. Levels of PACAP in both stressed and non-stressed female rats were not significantly different, however, both groups of females had PACAP levels that were higher than in either male group.
These exp'eriments provide evidence that BNST PACAP plays an important role in mediating behavioral and peripheral stress responses and is also involved in the enhanced BNST plasticity that may lead to disruption of both HPA-axis function and behavioral responding following exposure to stressors. This body of work helps to elucidate molecular underpinnings of anxiety-related pathology and has the potential to inform future therapeutics in the treatment of these disorders.