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)

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)