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Possible neuroinflammatory mechanisms involved in the extinction deficits of conditioning fear following exposing rats to a predator: the role of endocannabinoid system

Grant number: 11/22523-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2016
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Francisco Silveira Guimaraes
Grantee:Sabrina Francesca de Souza Lisboa
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:12/17626-7 - Cellular and molecular mechanisms involved in the role of atypical neurotransmitters in neuropsychiatric disorders, AP.TEM
Associated scholarship(s):14/21226-0 - Neuroinflammatory mechanisms involved in extinction deficits of fear conditioning induced by acute or repeated trauma exposure in mice, BE.EP.PD


The post-traumatic stress disorder (PTSD) is an anxiety disorder that can develop after exposure to a traumatic event. Among the pathophysiological factors involved in its genesis, it proposes changes in processes of fear conditioning (MC), in which its manifestations are exaggerated and resistant to extinction. The etiology and maintenance of this response have been related to alterations of multiple systems, including the hypothalamic-pituitary-adrenal axis, neurotransmitters such as serotonin, glutamate, endocannabinoids and nitric oxide. How these factors interact to produce this complex picture, however, remains poorly understood. A recent proposal is that immunological factors might be involved, since exposure to severe stressors, promoting activation of microglia and the transcription factor NF-º², can induce the expression, release and activity of various inflammatory mediators such as glutamate, nitric oxide and cytokines, which could induce neuroplastic changes responsible for the development of PTSD. There are several animal models proposed for PTSD and one of them is the exposure of rats to a natural predator (cat). This procedure induces in most animals (but not all) several changes observed in PTSD, such as increased contextual fear conditioning (CFC) and impaired extinction of aversive memory. The aim of this project is to investigate a possible involvement of immunological mechanisms in the development of behavioral changes related to PTSD. We will test the hypotheses that 1. animals that present fear behavior due to the presence of cat will present microglia activation and extinction deficit in the CFC, associated with a reduction in the increased levels of corticosterone and other regulatory mechanisms, and activation of inflammatory mechanisms in brain structures related to controlling the stress response, as well as decrease in plasmatic levels of tryptophan and an increase in its toxic metabolites, both resulting from IDO activation. Animals that do not show fear behaviuor does not present such changes. 2. Considering the evidence that facilitation of neurotransmission mediated by endocannabinoids attenuates the development of PTSD, we will verify if this signalling ameliorate the behavioral, immunological and neuro-hormonal-changes induced by exposure to a predator. An inhibitor of serotonin reuptake will be used as a positive control to behavioral alterations.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HARTMANN, ALICE; LISBOA, SABRINA FRANCESCA; SONEGO, ANDREZA BUZOLIN; COUTINHO, DEBORA; GOMES, FELIPE VILLELA; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 94, . (16/14282-6, 10/17343-0, 17/24304-0, 11/22523-0, 17/19731-6)
LISBOA, SABRINA F.; GOMES, FELIPE V.; SILVA, ANDREIA L.; ULIANA, DANIELA L.; CAMARGO, LAURA H. A.; GUIMARAES, FRANCISCO S.; CUNHA, FERNANDO Q.; JOCA, SAMIA R. L.; RESSTEL, LEONARDO B. M.. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 18, n. 8, . (11/22523-0)

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