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

Author(s)

Malta, Marilia B. ^[1] ; Martins, Joelcimar ^[2] ; Novaes, Leonardo S. ^[1] ; dos Santos, Nilton B. ^[1] ; Sita, Luciane ^[3] ; Camarini, Rosana ^[1] ; Scavone, Cristoforo ^[1] ; Bittencourt, Jackson ^{[4, 3]} ; Munhoz, Carolina D. ^{[4, 1, 2, 3]}

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Pharmacol, Lineu Prestes, 1524, room, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Cent Fac, Inst Ciencias Biomed, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Dept Anat, Lab Chem Neuroanat, Inst Ciencias Biomed, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Psychol, Ctr Neurosci & Behav, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 58, n. 10 JUL 2021.
• Web of Science Citations: 1

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. (AU)

• FAPESP's process: 12/24002-0 - Effects of environmental enrichment in long-lasting anxiety symptoms triggered by acute stress: implications in the emotional memory acquisition
• Grantee: Leonardo Santana Novaes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/02224-1 - The existence of neurogenesis during the lactation period
• Grantee: Jackson Cioni Bittencourt
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/24727-4 - Comparison of the therapeutical effects of dexamethasone (a synthetic glucocorticoid analogue), and G1 (a G-coupled estrogen receptor, GPER agonist) on the EAE-induced neuroinflammation
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/52068-0 - The putative envolvement of melanin-concentrating hormone in the control of lactation
• Grantee: Jackson Cioni Bittencourt
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/13843-8 - Protection conferred by environmental enrichment on stress-induced anxiety: the importance of GR, ERK, and CREB pathways in the rat basolateral amygdala
• Grantee: Leonardo Santana Novaes
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/03572-3 - The relationship between glucocorticoid receptor activation and the neuronal hyperexcitability in the basolateral amygdala in the restraint stress-induced long-lasting anxiety and their implications in the impaired contextual fear extinction
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Regular Research Grants