Journal
MOLECULAR NEUROBIOLOGY
Volume 58, Issue 10, Pages 4871-4885Publisher
SPRINGER
DOI: 10.1007/s12035-021-02470-2
Keywords
Chronic stress; Lateral septum; Glucocorticoids; Type-2 CRF receptor; Norepinephrine; Anxiety-like behavior
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Sao Paulo Research Foundation - FAPESP) [2010/52068-0, 2016/02224-1]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Agency for the Advancement of Higher Education)
- Comite Francais d'Evaluation de la Cooperation Universitaire avec le Bresil (French Committee for the Evaluation of Academic and Scientific Cooperation with Brazil) grant CAPES-COFECUB [848/15]
- National Council for Scientific and Technological Development-CNPq [426378/2016-4]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP: 2008/55178-0, 2012/24727-4, 2016/03572-3]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq: 479153/2009-4, 422523/2016-0]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
- FAPESP [2010/13843-8, 2012/24002-0, 2006/52566-4]
- CAPES
- CNPq [160570/2012-3]
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The stress response is a complex process involving multiple factors that mainly act through activating the HPA axis to produce a series of behavioral, endocrine, and autonomic changes. Ineffective self-regulation of stress can be harmful to the organism and predisposes it to pathologies. In the chronic unpredictable stress experimental model, CRF and GCs play crucial roles.
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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