Skip to main content
SpringerLink
Log in

Regulation of Bed Nucleus of the Stria Terminalis PACAP Expression by Stress and Corticosterone

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Single-nucleotide polymorphisms (SNPs) in the genes for pituitary adenylyl cyclase-activating peptide (PACAP) and the PAC1 receptor have been associated with stress-related psychiatric disorders. Although, from recent work, we have argued that stress-induced PACAP expression in the bed nucleus of the stria terminalis (BNST) may mediate stress-related psychopathology, it is unclear whether stress-induced increases in BNST PACAP expression require acute or repeated stressor exposure and whether increased BNST PACAP expression is related to stress-induced increases in circulating glucocorticoids. In the current work, we have used real-time quantitative polymerase chain reaction (qPCR) to assess transcript expression in brain punches from rats after stressor exposure paradigms or corticosterone injection. BNST PACAP and PAC1 receptor transcript expression was increased only after 7 days of repeated stressor exposure; no changes in transcript levels were observed 2 or 24 hours after a single-restraint session. Moreover, repeated corticosterone treatment for 7 days was not sufficient to reliably increase BNST PACAP transcript levels, suggesting that stress-induced elevations in corticosterone may not be the primary drivers of BNST PACAP expression. These results may help clarify the mechanisms and temporal processes that underlie BNST PACAP induction for intervention in stress-related anxiety disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Agarwal A, Halvorson LM, Legradi G (2005) Pituitary adenylate cyclase-activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: evidence for PKA-mediated expression of the corticotropin-releasing hormone (CRH) gene. Brain Res Mol Brain Res 138:45–57

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C (1991) Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129:2787–2789

    Article  CAS  PubMed  Google Scholar 

  • Barnum CJ, Eskow KL, Dupre K, Blandino P Jr, Deak T, Bishop C (2008) Exogenous corticosterone reduces L-DOPA-induced dyskinesia in the hemi-parkinsonian rat: role for interleukin-1beta. Neuroscience 156:30–41

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choi DC, Furay AR, Evanson NK, Ostrander MM, Ulrich-Lai YM, Herman JP (2007) Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs. J Neurosci 27:2025–2034

    Article  CAS  PubMed  Google Scholar 

  • Diniz L, Dos Reis BB, de Castro GM, Medalha CC, Viana MB (2011) Effects of chronic corticosterone and imipramine administration on panic and anxiety-related responses. Braz J Med Biol Res 44:1048–1053

    Article  CAS  PubMed  Google Scholar 

  • Girard BM, May V, Bora SH, Fina F, Braas KM (2002) Regulation of neurotrophic peptide expression in sympathetic neurons: quantitative analysis using radioimmunoassay and real-time quantitative polymerase chain reaction. Regul Pept 109:89–101

    Article  CAS  PubMed  Google Scholar 

  • Girard BA, Lelievre V, Braas KM, Razinia T, Vizzard MA, Ioffe Y, El Meskini R, Ronnett GV, Waschek JA, May V (2006) Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice. J Neurochem 99:499–513

    Article  CAS  PubMed  Google Scholar 

  • Groeneweg FL, Karst H, de Kloet ER, Joels M (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 209:153–167

    Article  CAS  PubMed  Google Scholar 

  • Hammack SE, Cheung J, Rhodes KM, Schutz KC, Falls WA, Braas KM, May V (2009) Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior. Psychoneuroendocrinology 34:833–843

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hammack SE, Roman CW, Lezak KR, Kocho-Shellenberg M, Grimmig B, Falls WA, Braas K, May V (2010) 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hannibal J, Mikkelsen JD, Fahrenkrug J, Larsen PJ (1995) Pituitary adenylate cyclase-activating peptide gene expression in corticotropin-releasing factor-containing parvicellular neurons of the rat hypothalamic paraventricular nucleus is induced by colchicine, but not by adrenalectomy, acute osmotic, ether, or restraint stress. Endocrinology 136:4116–4124

    CAS  PubMed  Google Scholar 

  • Hashimoto H, Shintani N, Tanaka K, Mori W, Hirose M, Matsuda T, Sakaue M, Miyazaki J, Niwa H, Tashiro F, Yamamoto K, Koga K, Tomimoto S, Kunugi A, Suetake S, Baba A (2001) Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP). Proc Natl Acad Sci U S A 98:13355–13360

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hashimoto H, Hashimoto R, Shintani N, Tanaka K, Yamamoto A, Hatanaka M, Guo X, Morita Y, Tanida M, Nagai K, Takeda M, Baba A (2009) Depression-like behavior in the forced swimming test in PACAP-deficient mice: amelioration by the atypical antipsychotic risperidone. J Neurochem 110:595–602

    Article  CAS  PubMed  Google Scholar 

  • Hattori S, Takao K, Tanda K, Toyama K, Shintani N, Baba A, Hashimoto H, Miyakawa T (2012) Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice. Front Behav Neurosci 6:58, eCollection

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Herman JP, Prewitt CM, Cullinan WE (1996) Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis. Crit Rev Neurobiol 10:371–394

    Article  CAS  PubMed  Google Scholar 

  • Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuro-Psychopharmacol Biol Psychiatry 29:1201–1213

    Article  CAS  Google Scholar 

  • Kalman BA, Spencer RL (2002) Rapid corticosteroid-dependent regulation of mineralocorticoid receptor protein expression in rat brain. Endocrinology 143:4184–4195

    Article  CAS  PubMed  Google Scholar 

  • Kocho-Schellenberg M, Lezak KR, Harris OM, Roelke E, Gick N, Choi I, Edwards S, Wasserman E, Toufexis DJ, Braas KM, May V & Hammack SE (2014) Pituitary adenylate cyclase activating peptide (PACAP) in the bed nucleus of the stria terminalis (BNST) produces anorexia and weight loss in male and female rats. Neuropsychopharmacology, in press

  • Kozicz T, Vigh S, Arimura A (1997) Axon terminals containing PACAP- and VIP-immunoreactivity form synapses with CRF-immunoreactive neurons in the dorsolateral division of the bed nucleus of the stria terminalis in the rat. Brain Res 767:109–119

    Article  CAS  PubMed  Google Scholar 

  • Légrádi G, Hannibal J, Lechan RM (1998) Pituitary adenylate cyclase-activating polypeptide-nerve terminals densely innervate corticotropin-releasing hormone-neurons in the hypothalamic paraventricular nucleus of the rat. Neurosci Lett 246:145–148

    Article  PubMed  Google Scholar 

  • Ma XM, Levy A, Lightman SL (1997) Rapid changes in heteronuclear RNA for corticotrophin-releasing hormone and arginine vasopressin in response to acute stress. J Endocrinol 152:81–89

    Article  CAS  PubMed  Google Scholar 

  • Makino S, Gold PW, Schulkin J (1994) Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 657:141–149

    Article  CAS  PubMed  Google Scholar 

  • McEwen BS (2008) Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol 583:174–185

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nomura M, Ueta Y, Serino R, Kabashima N, Shibuya I, Yamashita H (1996) PACAP type I receptor gene expression in the paraventricular and supraoptic nuclei of rats. Neuroreport 8:67–70

    Article  CAS  PubMed  Google Scholar 

  • Otto C, Kovalchuk Y, Wolfer DP, Gass P, Martin M, Zuschratter W, Grone HJ, Kellendonk C, Tronche F, Maldonado R, Lipp HP, Konnerth A, Schutz G (2001a) Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice. J Neurosci 21:5520–5527

    CAS  PubMed  Google Scholar 

  • Otto C, Martin M, Wolfer DP, Lipp HP, Maldonado R, Schutz G (2001b) Altered emotional behavior in PACAP-type-I-receptor-deficient mice. Brain research. Mol Brain Res 92:78–84

    Article  CAS  PubMed  Google Scholar 

  • Packan DR, Sapolsky RM (1990) Glucocorticoid endangerment of the hippocampus: tissue, steroid and receptor specificity. Neuroendocrinology 51:613–618

    Article  CAS  PubMed  Google Scholar 

  • Pego JM, Morgado P, Pinto LG, Cerqueira JJ, Almeida OFX, Sousa N (2008) Dissociation of the morphological correlates of stress-induced anxiety and fear. Eur J Neurosci 27:1503–1516

    Article  CAS  PubMed  Google Scholar 

  • Radley JJ, Sawchenko PE (2011) A common substrate for prefrontal and hippocampal inhibition of the neuroendocrine stress response. J Neurosci 31:9683–9695

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470:492–497

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roman CW, Lezak KR, Kocho-Schellenberg M, Garret MA, Braas K, May V, Hammack SE (2012) Excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) attenuate the effects of repeated stress on weight gain: evidence for the recruitment of BNST activity by repeated, but not acute, stress. Behav Brain Res 227:300–304

    Article  PubMed Central  PubMed  Google Scholar 

  • Schulkin J, Gold PW, McEwen BS (1998) Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load. Psychoneuroendocrinology 23:219–243

    Article  CAS  PubMed  Google Scholar 

  • Shepard JD, Schulkin J, Myers DA (2006) Chronically elevated corticosterone in the amygdala increases corticotropin releasing factor mRNA in the dorsolateral bed nucleus of stria terminalis following duress. Behav Brain Res 174:193–196

    Article  CAS  PubMed  Google Scholar 

  • Shepard JD, Chambers CO, Busch C, Mount A, Schulkin J (2009) Chronically elevated corticosterone in the dorsolateral bed nuclei of stria terminalis increases anxiety-like behavior. Behav Brain Res 203:146–149

    Article  CAS  PubMed  Google Scholar 

  • Shioda S, Shuto Y, Somogyvári-Vigh A, Legradi G, Onda H, Coy DH, Nakajo S, Arimura A (1997) Localization and gene expression of the receptor for pituitary adenylate cyclase-activating polypeptide in the rat brain. Neurosci Res 28:345–354

    Article  CAS  PubMed  Google Scholar 

  • Stroth N, Eiden LE (2010) Stress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling. Neuroscience 165:1025–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sullivan GM, Apergis J, Bush DE, Johnson LR, Hou M, Ledoux JE (2004) Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience 128:7–14

    Article  CAS  PubMed  Google Scholar 

  • Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10:397–409

    Article  CAS  PubMed  Google Scholar 

  • Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357

    Article  CAS  PubMed  Google Scholar 

  • Vyas A, Bernal S, Chattarji S (2003) Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res 965:290–294

    Article  CAS  PubMed  Google Scholar 

  • Waddell J, Morris RW, Bouton ME (2006) Effects of bed nucleus of the stria terminalis lesions on conditioned anxiety: aversive conditioning with long-duration conditional stimuli and reinstatement of extinguished fear. Behav Neurosci 120:324–336

    Article  PubMed  Google Scholar 

  • Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463:199–216

    Article  CAS  PubMed  Google Scholar 

  • Watts AG, Sanchez-Watts G (1995) Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and corticosterone. J Physiol 484:721–736

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants MH-97988, MH-072088, and MH-096764 from the National Institutes of Health. Portions of the work were also supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the University of Vermont College of Arts and Sciences as well as funds from the Center of Biomedical Research Excellence (COBRE) in Neuroscience at the University of Vermont (National Institute of Health NCRR P20RR16435). We are grateful to Terrence Deak and Cara Hueston for their assistance with this project.

Author information

Authors and Affiliations

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

    Kimberly R. Lezak, Carolyn W. Roman, William A. Falls & Sayamwong E. Hammack

  2. Department of Neurological Sciences, College of Medicine, University of Vermont, 149 Beaumont Avenue, Burlington, VT, 05405, USA

    Carolyn W. Roman, Karen M. Braas, Kristin C. Schutz & Victor May

  3. Department of Neuroscience, Georgetown University, 3970 Reservoir Road. NW, NRB, Washington, DC, 20057, USA

    Jay Schulkin

Authors
  1. Kimberly R. Lezak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carolyn W. Roman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen M. Braas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristin C. Schutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William A. Falls
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jay Schulkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Victor May
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sayamwong E. Hammack
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kimberly R. Lezak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lezak, K.R., Roman, C.W., Braas, K.M. et al. Regulation of Bed Nucleus of the Stria Terminalis PACAP Expression by Stress and Corticosterone. J Mol Neurosci 54, 477–484 (2014). https://doi.org/10.1007/s12031-014-0269-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0269-8

Keywords

Search

Navigation