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Genetic study of hypocampus glutamate neurotransmission in central mechanisms of the adaptation of neuroendocrine, cardiovascular and behavioral responses to repeated chronic stress and stress-induced neuroinflamation

Grant number: 18/04899-1
Support type:Research Grants - Young Investigators Grants
Duration: February 01, 2021 - January 31, 2026
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Cristiane Busnardo Santiago
Grantee:Cristiane Busnardo Santiago
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Assoc. researchers:Carlos Cesar Crestani ; Fabio Cardoso Cruz ; Fernando Morgan de Aguiar Correa ; James Paul Herman

Abstract

Emotional stress has caused a physiological and psychological imbalance, and it has been associated with several pathologies, including cardiovascular diseases and psychiatric disorders. Adaptive processes are triggered during prolonged or repeated exposure to stress, in which they are important to minimize the impact of stress on the body. An important adaptation is a habituation of physiological responses (e.g., hypothalamic-pituitary-adrenal (HPA) axis stimulation and neural activation) during a repeated exposure to the same aversive stimulus. However, despite the importance of habituation of stress responses, the neurobiological and neurochemical mechanisms involved in this process are still poorly understood. In this sense, it has been demonstrated a functional interaction between glutamatergic and nitrergic neurotransmissions in the hippocampus in the regulation of autonomic, HPA axis and / or behavioral responses to acute stress. However, a possible involvement of this signaling mechanism in the habituation process during repeated exposure to stress situations has never been investigated. In addition, glucocorticoids and neurotransmitters such as glutamate released into the central nervous system (CNS) during stress induce a local release of proinflammatory cytokines, which may lead to long-term behavioral consequences, such as depressive-type behaviors, being considered a poor adaptation to stress. So, the study of cytokine release is essential for understanding the effects of stress on the CNS. Therefore, the goal of the present project is to evaluate the effect of chemogenic silencing (through the use of DREADDs) of glutamatergic neurons in the ventral and dorsal hippocampus on habituation of autonomic, neuroendocrine, behavioral and neuroinflammatory responses related to exposure restraint stress. As a DREADD technology is used to inactivate glutamatergic neurons independent of their activation state, it will be also used the Daun02 inactivation method in transgenic c-Fos lacZ rat that inactivates only neurons that were previously activated during a specific behavior. In this sense, we will also evaluate the inactivation of ventral and dorsal hippocampal neurons previously activated by restraint stress on the habituation of autonomic, neuroendocrine, behavioral and neuroinflammatory responses associated with chronic restraint stress. (AU)