Functional lateralization assessment in the control of cardiovascular and behavioral responses to contextual fear conditioning by the medial prefrontal cortex in rats

• Grant number: 22/06260-3
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2023 - January 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Ricardo Luiz Nunes de Souza
• Grantee: Ricardo Luiz Nunes de Souza
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Cristiane Busnardo Santiago ; Fabio Cardoso Cruz ; Leonardo Resstel Barbosa Moraes ; Nuno Jorge Carvalho de Sousa

Abstract

Exposure to stressful events has been related to the etiology of several diseases, including cardiovascular and neuropsychiatric diseases such as anxiety and depression. Despite the relevance of the topic, the neurobiological mechanisms involved in cardiovascular complications and psychiatric disorders induced by stress, as well as the possible relationship between these diseases, are still poorly understood. The medial prefrontal cortex (mPFC) is a limbic structure that is involved in the expression of physiological and behavioral responses to various stressors, including conditioned aversive stimuli, such as those triggered by contextual fear conditioning (CFC). A relevant aspect regarding the mPFC is the evidence of functional lateralization in the control of responses to aversive stimuli. In this sense, results from previous studies have indicated that the right mPFC (RmPFC) seems to be more directly related to the expression of physiological and behavioral responses during stress situations, while the left mPFC (LmPFC) would have a counter-regulatory role by inhibiting the RmPFC. Despite this evidence, a possible lateralization in the control of CFC responses by mPFC has never been documented. In this sense, a first hypothesis to be tested in the present study is that the control of freezing and cardiovascular responses of the CFC by the mPFC occurs in a lateralized manner. Despite the well-established involvement of mPFC in the expression of conditioned physiological and behavioral responses in the CFC, the local neurochemical mechanisms involved are still poorly understood. In this sense, the presence of peptides from the corticotropin-releasing factor (CRF) system in GABAergic interneurons and axon terminals, as well as of CRFergic receptors, has been reported in the mPFC. Despite evidence that aversive stimuli activate neurons that express CRF and increase the local release of CRF within the mPFC, a role of this neurochemical mechanism in the control of cardiovascular and freezing responses of the CFC by the mPFC has never been reported. Thus, a second hypothesis to be investigated in the present study is that the control of cardiovascular and freezing responses of the CFC by the mPFC is mediated by local CRFergic neurotransmission. We will also evaluate the role of CRFergic neurotransmission in an eventual lateralization of the control of responses to the CFC by the mPFC. Finally, a lateralization in the morphological consequences in the mPFC resulting from chronic exposure to stressful stimuli was also reported, so that the LmPFC seems to be more affected. It is also well described in the literature that exposure to chronic stressors before training in conditioning models increases fear memory and, consequently, conditioned defensive responses. Although the involvement of CRFergic neurotransmission in the mPFC in influence of chronic stress on conditioned aversive responses has never been reported, the hypothesis of a participation of this neurochemical mechanism in the mPFC is supported by previous evidence that the increase in the conditioned freezing response in animals subjected to a protocol of chronic variable stress (CVS) was accompanied by increase in CRF1 receptor mRNA levels in the mPFC. Thus, a last hypothesis to be investigated is that CRFergic neurotransmission in the mPFC is involved in local morphological changes and in the facilitation of responses to the CFC resulting from previous exposure to a CVS protocol, and this participation occurs in a lateralized manner. (AU)