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Norepinephrine and Glucocorticoids Modulate Chronic Unpredictable Stress-Induced Increase in the Type 2 CRF and Glucocorticoid Receptors in Brain Structures Related to the HPA Axis Activation

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Abstract

The stress response is multifactorial and enrolls circuitries to build a coordinated reaction, leading to behavioral, endocrine, and autonomic changes. These changes are mainly related to the hypothalamus–pituitary–adrenal (HPA) axis activation and the organism’s integrity. However, when self-regulation is ineffective, stress becomes harmful and predisposes the organism to pathologies. The chronic unpredictable stress (CUS) is a widely used experimental model since it induces physiological and behavioral changes and better mimics the stressors variability encountered in daily life. Corticotropin-releasing factor (CRF) and glucocorticoids (GCs) are deeply implicated in the CUS-induced physiological and behavioral changes. Nonetheless, the CUS modulation of CRF receptors and GR and the norepinephrine role in extra-hypothalamic brain areas were not well explored. Here, we show that 14 days of CUS induced a long-lasting HPA axis hyperactivity evidenced by plasmatic corticosterone increase and adrenal gland hypertrophy, which was dependent on both GCs and NE release induced by each stress session. CUS also increased CRF2 mRNA expression and GR protein levels in fundamental brain structures related to HPA regulation and behavior, such as the lateral septal nucleus intermedia part (LSI), ventromedial hypothalamic nucleus (VMH), and central nucleus of the amygdala (CeA). We also showed that NE participates in the CUS-induced increase in CRF2 and GR levels in the LSI, reinforcing the locus coeruleus (LC) involvement in the HPA axis modulation. Despite the CUS-induced molecular changes in essential areas related to anxiety-like behavior, this phenotype was not observed in CUS animals 24 h after the last stress session.

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Data Availability (Data Transparency)

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Acknowledgements

We gratefully thank Guiomar Wiesel and Larissa de Sá Lima for technical assistance.

Funding

This article was supported by research grants to J.B. from Fundação de Amparo à Pesquisa do Estado de São Paulo (São Paulo Research Foundation — FAPESP) grants #2010/52068–0, #2016/02224–1. J.B. was also supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Agency for the Advancement of Higher Education) and Comité Français d’Evaluation de la Coopération Universitaire avec le Brésil (French Committee for the Evaluation of Academic and Scientific Cooperation with Brazil) grant CAPES-COFECUB 848/15. J.B. is an Investigator with the Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development— CNPq) with grant # #426378/2016–4. This work was supported by research grants to C.D.M. from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP: 2008/55178–0, 2012/24727–4, and 2016/03572–3) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq: 479153/2009–4 and 422523/2016–0). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. M.B.M. was supported by FAPESP (2006/52566–4) and CAPES. L.S.N. was supported by FAPESP (2010/13843–8 and 2012/24002–0). N.B.S. was supported by CNPq (160570/2012–3); C.D.M., C.S., and R.C. are research fellows from CNPq.

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Authors and Affiliations

  1. Department of Pharmacology, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, Av. Prof. Lineu Prestes, 1524, room 323, São Paulo, SP, 05508-000, Brazil

    Marilia B. Malta, Leonardo S. Novaes, Nilton B. dos Santos, Rosana Camarini, Cristoforo Scavone & Carolina D. Munhoz

  2. Central of Facilities, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, 05508-000, Brazil

    Joelcimar Martins

  3. Laboratory of Chemical Neuroanatomy, Department of Anatomy, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, São Paulo, 05508-000, Brazil

    Luciane Sita & Jackson Bittencourt

  4. Center for Neurosciences and Behavior, Institute of Psychology, University of São Paulo, São Paulo, 05508-000, Brazil

    Jackson Bittencourt

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  1. Marilia B. Malta
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Contributions

M.B.M. designed research, performed research, analyzed data, wrote the paper, revised the paper final version; J.M. designed research, performed research, revised the paper final version; L.S.N. performed research, analyzed data, revised the paper final version; N.B.S. performed research, analyzed data, revised the paper final version; L.S. analyzed data, contributed unpublished reagents/analytic tools, revised the paper final version; R.C: contributed unpublished reagents/analytic tools, revised the paper final version; C.S. contributed unpublished reagents/analytic tools, analyzed data, revised the paper final version; J.B. contributed unpublished reagents/analytic tools, analyzed data, revised the paper final version; C.D.M.: designed research, analyzed data, contributed unpublished reagents/analytic tools, wrote the paper and revised the paper final version.

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Correspondence to Carolina D. Munhoz.

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All animals were used following the standards of the Ethics Committee for Animal Use of the Institute of Biomedical Sciences/University of São Paulo (CEUA- ICB 102/06 and 75/05) and the guidelines of the Brazilian National Council for the Control of Animal Experimentation (CONCEA).

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Malta, M.B., Martins, J., Novaes, L.S. et al. Norepinephrine and Glucocorticoids Modulate Chronic Unpredictable Stress-Induced Increase in the Type 2 CRF and Glucocorticoid Receptors in Brain Structures Related to the HPA Axis Activation. Mol Neurobiol 58, 4871–4885 (2021). https://doi.org/10.1007/s12035-021-02470-2

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