Evaluation of the possible facilitation of the response to the extinguishment of conditioned fear after trauma by drugs that alter epigenetic mechanisms

• Grant number: 21/02139-2
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): April 01, 2021
• Effective date (End): June 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal researcher: Sabrina Francesca de Souza Lisboa
• Grantee: Larissa Menegassi
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/19731-6 - 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), AP.JP

Abstract

Posttraumatic stress disorder (PTSD) is a chronic and debilitating neuropsychiatric disorder associated with trauma and stress. Among symptoms, we can cite the impaired ability to extinguish aversive memories. PTSD occurs when a biological predisposition coincides with a traumatic stressor, thus assuming that the epigenome may contribute to its pathogenesis since it can mediate communication between the environment and genome. Epigenetic mechanisms can explain how trauma causes long-term changes through exposure to stressors and how it influences the processing of aversive memories in brain structures involved in these processes. The consolidation of long-term fear extinction memories requires protein synthesis. This process involves the coordinated transcription of specific genes coding for learning associated transcription factors, neurotransmitter receptors, cytoskeletal proteins, and other cellular substrates. Histone acetylation is a mechanism that accompanies different forms of learning and memory. Changes in acetylation during or after learning or extinguishing fear occur in learning-associated areas such as the hippocampus, amygdala, and prefrontal cortex. Therefore, the increase in histone acetylation induced by fear extinction may be a coordinated synergistic response of enhancing HAT (histone acetyltransferase) activity and reduction in HDAC (histone deacetylases) activity in specific brain areas. Stress exposure can also activate the enzymes DNA methyltransferases (DNMT), which trigger a methyl group's binding to DNA, blocking the binding of the transcription machinery to DNA and recruiting transcription repressors. Thus, it is crucial to assess whether the administration of HDAC or DNMT inhibitor associated with the extinction process in animal models could facilitate this process, this being our first objective. In addition to the epigenetic mechanisms, changes in the endocannabinoid system can also be observed in PTSD, capable of modulating several brain functions, including emotional memory. These changes could be partly due to epigenetic changes. ECBs are produced in response to stress and act on cannabinoid type 1 (CB1) and type 2 (CB2) receptors. The enzymes FAAH (Fatty Acid Amide Hydrolase) and MGL (monoacylglycerol lipase) combined with cannabinoid receptors are essential for forming, maintaining, and extinct aversive/traumatic memory. Patients with PTSD present enhanced methylation of the CB1 gene and decreased methylation of genes related to the immune response. Thus, it is essential to assess whether the possible facilitation of extinction induced by drugs that modulate epigenetics involves changes in the levels of molecules related to the endocannabinoid system, verified in this project.