Study of the involvement of CRF binding protein (CRFBP) into medial prefrontal cortex (mPFC) on control of cardiovascular, neuroendocrine and behavioral responses evoked by acute and chronical psychological stress in rats

• Grant number: 19/25035-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2022
• End date: August 29, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Carlos Cesar Crestani
• Grantee: Leandro Augusto de Oliveira
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 23/00282-8 - Role of corticolimbic glucocorticoid receptor signaling in traumatic stress pathology, BE.EP.PD

Abstract

The medial prefrontal cortex (MPFC) is a limbic region located in the telencephalon, which is implicated in the control of cardiovascular, neuroendocrine and behavioral responses to stress. However, the local neurochemical mechanisms, especially neuropeptidergic, associated with stress response control by the MPFC are still poorly understood. The wide distribution of CRF-binding protein (CRF-BP) throughout the brain in humans and rodents, including MPFC, is well described. The neuropeptide corticotropin-releasing factor (CRF) has also been identified in cortical interneurons. In addition, CRF and urocortin 1 were identified at terminals in the MPFC. Regarding the receptors, rodent CPFM has been reported to predominantly express the CRF1 receptor, but some studies have reported CRF2 receptor expression in the prefrontal cortex of non-human and human primates and rodents. Stress activates neurons that express CRF within MPFC, and MPFC CRFergic neurotransmission has been reported to be involved in the expression of anxiety-related behaviors as well as in cognitive impairments caused by stress. Despite this evidence, in a broad literature search we have not found studies that have evaluated a possible role of CRF-BP in the MPFC in the control of physiological and behavioral responses induced by aversive stimuli. In addition, the possible participation of "CRFergic" neurotransmission in the MPFC in controlling cardiovascular function at rest or during exposure to aversive stimuli has never been explored. Also, despite evidence of CRF2 receptor expression in the MPFC, the involvement of this receptor within the CPFM in controlling stress responses has never been evaluated. The social defeat witness model consists of an alternative approach using the experimental model of social defeat, in which an animal named "witness" witnesses aggressive social interaction between co-specifics, but with no physical contact. This model is described as an alternative that allows the evaluation of the psychological component of the social defeat, without interference of the physical components inherent to aggressive interactions. Thus, the present study has the following objectives: 1) to evaluate the role of CRF-BP in the MPFC on cardiovascular, neuroendocrine and behavioral responses triggered by an acute session of witnesses to social defeat, and to compare with the control exerted by local CRF1 and CRF2 receptors; 2) to investigate whether CRF-BP in the MPFC would act as a CRF / UCN scavenger or as a facilitative modulator of CRFergic neurotransmission in the control of cardiovascular, neuroendocrine and behavioral responses caused by an acute session of witness to social defeat. 3) to evaluate the role of PL-CRF in the MPFC on cardiac, autonomic, neuroendocrine and behavioral changes triggered by chronic exposure to witness to social defeat, and compare with the control exerted by local CRF1 and CRF2 receptors; 4) to investigate the effect of acute session of witness to social defeat on the CRF-BP and CRF1 and CRF2 receptors mRNA in the MPFC; as well as the consequences of chronic exposure to this stressor on protein levels of CRF-BP and CRF1 and CRF2 receptors in MPFC. (AU)