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Roles for Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Expression and Signaling in the Bed Nucleus of the Stria Terminalis (BNST) in Mediating the Behavioral Consequences of Chronic Stress

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Abstract

Anxiety disorders are frequently long-lasting and debilitating for more than 40 million American adults. Although stressor exposure plays an important role in the etiology of some anxiety disorders, the mechanisms by which exposure to stressful stimuli alters central circuits that mediate anxiety-like emotional behavior are still unknown. Substantial evidence has implicated regions of the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala as critical structures mediating fear- and anxiety-like behavior in both humans and animals. These areas organize coordinated fear- and anxiety-like behavioral responses as well as peripheral stress responding to threats via direct and indirect projections to the paraventricular nucleus of the hypothalamus and brainstem regions (Walker et al. Eur J Pharmacol 463:199–216, 2003, Prog Neuropsychopharmacol Biol Psychiatry 33(8):1291–1308, 2009; Ulrich-Lai and Herman Nat Rev Neurosci 10:397–409, 2009). In particular, the BNST has been argued to mediate these central and peripheral responses when the perceived threat is of long duration (Waddell et al. Behav Neurosci 120:324–336, 2006) and/or when the anxiety-like response is sustained (Walker and Davis Brain Struct Funct 213:29–42, 2008); hence, the BNST may mediate pathological anxiety-like states that result from exposure to chronic stress. Indeed, chronic stress paradigms result in enhanced BNST neuroplasticity that has been associated with pathological anxiety-like states (Vyas et al. Brain Res 965:290–294, 2003; Pego et al. Eur J Neurosci 27:1503–1516, 2008). Here we review evidence that suggests that pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing hormone (CRH) work together to modulate BNST function and increase anxiety-like behavior. Moreover, we have shown that BNST PACAP as well as its cognate PAC1 receptor is substantially upregulated following chronic stress, particularly in the BNST oval nucleus where PACAP-containing neurons closely interact with CRH-containing neurons (Kozicz et al. Brain Res 767:109–119, 1997; Hammack et al. Psychoneuroendocrinology 34:833–843, 2009). We describe how interactions between PACAP and CRH in the BNST may mediate stress-associated behaviors, including anorexia and anxiety-like behavior. These studies have the potential to define specific mechanisms underlying anxiety disorders, and may provide important therapeutic strategies for stress and anxiety management.

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Acknowledgments

This work was supported by grants HD27468 and NS37179 (VM and KMB), and MH072088 (SEH) from the National Institutes of Health. Portions of the work were also supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD). The use of the Molecular Biology Core Facility at the University of Vermont College of Medicine supported by National Institute of Health NCRR P20RR16435 is also gratefully acknowledged.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, University of Vermont College of Medicine, 149 Beaumont Avenue, HSRF 428, Burlington, VT, 05405, USA

    Carolyn W. Roman, Karen Braas & Victor May

  2. Department of Psychology, University of Vermont, 2 Colchester Avenue, Dewey Hall 334, Burlington, VT, 05405, USA

    Sayamwong E. Hammack, Carolyn W. Roman, Kimberly R. Lezak, Margaret Kocho-Shellenberg, Bethany Grimmig & William A. Falls

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  1. Sayamwong E. Hammack
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  2. Carolyn W. Roman
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  4. Margaret Kocho-Shellenberg
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  7. Karen Braas
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  8. Victor May
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Correspondence to Sayamwong E. Hammack or Victor May.

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Hammack, S.E., Roman, C.W., Lezak, K.R. et al. Roles for Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Expression and Signaling in the Bed Nucleus of the Stria Terminalis (BNST) in Mediating the Behavioral Consequences of Chronic Stress. J Mol Neurosci 42, 327–340 (2010). https://doi.org/10.1007/s12031-010-9364-7

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  • DOI: https://doi.org/10.1007/s12031-010-9364-7

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