Study of the role of Corticotropin Releasing Factor (CRF) neurotransmission in the insular cortex in the control of cardiovascular and anxiogenic responses to stress in rats

• Grant number: 20/15352-3
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2021
• Effective date (End): April 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Carlos Cesar Crestani
• Grantee: Lilian Liz Reis Silva
• Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Stress is identified as a risk factor for the development of several diseases, but the neurobiological mechanisms involved are not fully understood. In this sense, the insular cortex (IC) is involved in the integration and processing of limbic information in humans and animals, and its involvement in physiological and behavioral responses to stress has been reported. However, the neurochemical mechanisms involved in the control of stress responses by the IC is little understood. In this sense, the neurotransmission of the corticotropin-releasing factor (CRF) has been reported to be an important neurochemical mechanism in the central nervous system involved in the etiology of behavioral and physiological changes observed during exposure to aversive situations. Nevertheless, the specific brain sites whereby CRF neurotransmission acts to control stress responses are still poorly understood. Terminals containing CRF, as well as the CRF1 receptor, were identified in the IC. However, a possible involvement of this neurochemical mechanism within the IC in the control of stress-induced physiological and behavioral responses has never been investigated. Thus, the general proposal of the present study is to investigate the involvement of the CRF neurotransmission within the IC, acting through local CRF1 receptor, in the control of cardiovascular and anxiogenic responses evoked by restraint stress in rats. Human and animal studies have reported functional dissociation along the antero-posterior axis of the IC in control of cardiovascular function and sensitive responses. However, a possible rostro-caudal organization in the regulation of stress responses by the IC was never investigated. Thus, a hypothesis to be investigated in the present study is that the control of cardiovascular and anxiogenic responses to restraint stress by CRFergic neurotransmission occurs in a site-specific manner along the antero-posterior axis in the IC. It has also been reported that repeated exposure to aversive events alters the expression of the CRF and CRF1 receptor in several limbic structures. However, a possible effect of chronic stress on CRFergic neurotransmission in the IC has never been investigated. Thus, another hypothesis to be tested in the present study is that repeated exposure to restraint stress causes changes in CRF neurotransmission in the IC, and these changes affect the control of cardiovascular and anxiogenic responses to restraint stress by this neurochemical mechanism in the IC. In addition to cardiovascular and behavioral measurements, to characterize the local effects of CRFergic neurotransmission within the IC that might be related to the control of stress responses we will evaluate the effect of the CRF1 receptor antagonism within the IC on local neuronal activation in sub-regions along the antero-posterior axis of this cortical structure after an acute session and the 10th session of restraint stress; as well as the effect of repeated exposure to restraint stress on CRF1 receptor and CRF levels along the antero-posterior axis of the IC.