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Evaluation of the involvement of histone acetylation in behavioral changes and in the endocannabinoid system after exposure to trauma in mice

Grant number: 21/01656-3
Support type:Scholarships in Brazil - Master
Effective date (Start): April 01, 2021
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Sabrina Francesca de Souza Lisboa
Grantee:Arthur Alves Coelho
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
Associated scholarship(s):21/13878-0 - Possible involvement of the endocannabinoid and epigenetic mechanisms in the treatment-resistant behaviors induced in Flinders sensitive line rats by exposure to a traumatic stressor, BE.EP.MS


Post-traumatic stress disorder (PTSD) can develop after exposure to severe trauma, resulting in debilitating symptoms, such as difficulty in extinguishing aversive memories. Given this, the main therapy is cognitive-behavioral therapy (CBT) to facilitate the extinction of these memories. However, despite the severity of PTSD, CBT, as well as pharmacotherapy, or their combination, are ineffective in many patients. Also, pharmacotherapy is quite limited. These facts demonstrate the need to identify mechanisms altered by trauma that could serve as biomarkers and thus indicate new therapeutic targets to be explored. Within this context, the endocannabinoid system stands out for being altered in response to trauma in humans and animal models, and for being a very important system in responding to stress and facilitating fear extinction. Besides, studies demonstrate that epigenetic mechanisms (post-transcriptional or post-translational changes, in DNA or histone proteins, that alter gene expression without changing the DNA sequence, converting transient signals into long-lasting cellular responses) can regulate the expression of mediators of this system. In particular, changes in the histone acetylation process, caused by a combination of increased activity of HAT enzymes (histone acetyltransferase), and reduced activity of HDAC (histone deacetylases), during or after traumatic situations can occur in important brain areas to learning, such as the hippocampus, amygdala and prefrontal cortex, deregulating the processes that happen there and, consequently, contributing to the development of behavioral consequences resulting from stress. Thus, this project aims to assess whether the development of behavioral consequences resulting from exposure to trauma is associated with changes in histone protein acetylation mechanisms, particularly related to molecules of the endocannabinoid system, involved in maintaining synaptic homeostasis after stress. Also, experiments will be carried out to verify whether the pharmacological inhibition of enzymes that promote histone deacetylation is capable of preventing the long-term consequences of exposure to trauma. (AU)

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