Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat the posttraumatic stress disorder (PTSD)

• Grant number: 17/19731-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2019
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Sabrina Francesca de Souza Lisboa
• Grantee: Sabrina Francesca de Souza Lisboa
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Francisco Silveira Guimaraes ; John F Sheridan ; Jonathan Godbout ; Leonardo Resstel Barbosa Moraes ; Sâmia Regiane Lourenço Joca
• Associated scholarship(s): 24/05428-3 - A study on CaMKII involvement in behavioral and molecular alterations in iNOS knockout mice, BP.MS; 24/02917-3 - Training in techniques for care, maintenance and reproduction of transgenic lines of Cre-LoxP mice, BP.TT; 24/00146-0 - Training in cell culture techniques, BP.TT; + associated scholarships 23/01933-2 - Involvement of Toll-like receptors 4 (TLR4) located in microglial cells in the behavioral consequences of stress exposure in mice, BP.MS; 23/01686-5 - Effects of neuronal nitric oxide synthase inhibition on susceptibility to the development of anorexia nervosa-related behaviors in animals exposed to maternal deprivation., BP.IC; 22/10801-0 - Investigation of the effects of IL-1B on neuroplasticity and the Endocannabinoid System of hippocampal neurons, BP.MS; 23/01328-1 - Investigation of P2X7 receptors and the NLRP3 inflammasome in the extinction deficits observed in a genetic model of PTSD, BP.IC; 22/12981-5 - Training in techniques for care, maintenance and reproduction of transgenic lines of Cre-LoxP mice, BP.TT; 22/09921-0 - Investigation of cannabinoid mechanisms involved in extinction deficits in iNOS KO animals, a genetic model of PTSD, BP.IC; 22/00885-1 - Training in cell culture techniques, BP.TT; 21/08569-9 - Training in cell culture techniques., BP.TT; 21/05406-1 - Study of possible changes in the endocannabinoid, endovaniloid, and neuroimmune systems in brain after stimulation of microglia cells: involvement of epigenetic mechanisms, BP.MS; 21/01656-3 - Evaluation of the involvement of histone acetylation in behavioral changes and in the endocannabinoid system after exposure to trauma in mice, BP.MS; 21/02139-2 - Evaluation of the possible facilitation of the response to the extinguishment of conditioned fear after trauma by drugs that alter epigenetic mechanisms, BP.IC; 21/00335-9 - Training in techniques for care, maintenance and reproduction of transgenic lines of Cre-LoxP mice, BP.TT; 20/15951-4 - Training in cell culture techniques, BP.TT; 19/19226-5 - Evaluation of the involvement of endovanilloid and endocannabinoid systems in behavioral and plastic consequences after trauma exposure in mice, BP.MS; 19/12830-4 - Evaluation of the possible facilitation of the conditioned fear extinction response after trauma by drugs that modulate the endocannabinoid signaling, BP.IC; 18/24140-0 - Evaluation of P2X7-induced inflammasome activation and microglia M1/M2 polarization in an animal model of treatment-resistant depression, BP.PD; 19/05013-0 - Identification of epigenetic mechanisms induced by stress which modulate endocannabinoid signaling and neuroimmunological mechanisms as new therapeutic targets to treat posttraumatic stress disorder (PTSD)., BP.JP - associated scholarships

Abstract

The posttraumatic stress disorder (PTSD) can be developed after exposure to severe trauma, resulting in debilitating symptoms, such as impaired ability to extinguish aversive memories. Notwithstanding the PTSD severity, the pharmacotherapy is limited and inefficacious in several patients, evidencing the need for identification of trauma-altered mechanisms which could act as biomarkers, in order to provide potential novel therapeutic targets. The neuroimmune and endocannabinoid (ECB) systems are altered in response to trauma exposure in humans and animal models. Evidence suggests interaction between those systems in the modulation of the stress response, such as modulation of microglial activation and synaptic plasticity, which could result in dysfunctional synapses. One of the alterations in the microglia which may contribute to these effects is the activation of the NLRP3 inflammasome. Epigenetic mechanisms can modulate the expression of mediators from neuroimmune and ECB systems, contributing to the development of behavioral consequences of trauma exposure. The aim of this project is to investigate if trauma-induced high levels of ECBs and microglial NLRP3 inflammasome activation modulate the ECB system and alter the synaptic plasticity and activity, resulting in behavioral deficits. Moreover, the participation of epigenetic mechanisms in such effects will also be investigated. We will use in vitro e in vivo approaches to study molecular mechanisms, as well as behavioral and neuroplastic changes in naïve and stressed mice. To do that, we intend to perform pharmacological modulation of ECB signaling and epigenetic mechanisms, genetically modified mice, and cutting edge technologies on molecular biology. The results from this study may contribute to a better comprehension of PTSD neurobiology and, potentially, provide biomarkers after trauma exposure. Moreover, results could point out therapeutic alternatives for PTSD treatment in those patients that are resistant to conventional treatment. (AU)

Scientific publications

(6)

(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, AUG 30 2019. (16/14282-6, 10/17343-0, 17/24304-0, 11/22523-0, 17/19731-6)

BORGES-ASSIS, ANNA BARBARA; ULIANA, DANIELA LESCANO; HOTT, SARA CRISTINA; GUIMARA, FRANCISCO SILVEIRA; LISBOA, SABRINA FRANCESCA; RESSTEL, LEONARDO BARBOSA MORAES. Bed nucleus of the stria terminalis CB1 receptors and the FAAH enzyme modulate anxiety behavior depending on previous stress exposure. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 125, p. 12-pg., 2023-07-13. (17/16913-6, 17/24304-0, 12/17626-7, 17/19731-6)

SANADGOL, NIMA; FERIZ, ADIB MIRAKI; LISBOA, SABRINA F.; JOCA, SAMIA R. L.. Putative role of glial cells in treatment resistance depression: An updated critical literation review and evaluation of single-nuclei transcriptomics data. Life Sciences, v. 331, p. 12-pg., 2023-08-28. (17/24304-0, 18/24140-0, 17/19731-6)

PAGLIUSI, MARCO; AMORIM-MARQUES, ANNA P.; LOBO, MARY KAY; GUIMARAES, FRANCISCO S.; LISBOA, SABRINA F.; GOMES, FELIPE V.. The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress. Pain, v. 165, n. 8, p. 10-pg., 2024-08-01. (20/08363-9, 17/19731-6, 18/17597-3)

HARTMANN, ALICE; FASSINI, ALINE; SCOPINHO, AMERICA; CORREA, FERNANDO M. A.; GUIMARAES, FRANCISCO S.; LISBOA, SABRINA F.; RESSTEL, LEONARDO B. M.. Role of the endocannabinoid system in the dorsal hippocampus in the cardiovascular changes and delayed anxiety-like effect induced by acute restraint stress in rats. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 5, p. 606-614, MAY 2019. (17/19731-6, 16/14282-6, 13/13721-8, 14/24828-0, 12/17626-7, 13/00249-9)

SILVEIRA, KENNIA M. M.; SARTIM, ARIANDRA G. G.; VIEIRA, LETICIA; LISBOA, SABRINA F. F.; WEGENER, GREGERS; JOCA, SAMIA R. L.. Decreased sensitivity to antidepressant drugs in Wistar Hannover rats submitted to two animal models of depression. ACTA NEUROPSYCHIATRICA, v. N/A, p. 15-pg., 2022-09-14. (17/24304-0, 17/19731-6, 19/04616-2)