Pre-clinical model of social isolation in the discovery of the role of allopregnanolone in the inflammatory physiopathology of reproductive and non-reproductive tissues

• Grant number: 20/06364-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): October 01, 2020
• Effective date (End): December 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Maria Christina Werneck de Avellar
• Grantee: Luiz Gustavo Ferreira Fressatti
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Social isolation stress is recognized as a major morbidity risk factor in humans, exerting damaging effects for physical and mental health. Posttraumatic stress disorder (PTSD) occurs as a result of experiencing life-threatening, traumatic events, with involuntary re-experiencing trauma, avoidance symptoms, and distortions of cognition and emotional arousal. This is a neuropsychiatric condition that may persists for years, causing distress and severe impairment of day-to-day functioning. Social isolation has been associated with the predisposition, onset and outcome of PTSD and it is a preclinical model for this clinical condition. Levels of the steroid allopregnanolone (ALLO), that positively and allosterically modulate the action of GABA at GABAA receptors, are reduced in the cerebrospinal fluid of PTSD patients. In socially isolated mouse, and other PTSD animal models, reduced ALLO concentration in corticolimbic areas is also correlated with PTSD-related neurobiological and behavioral outcomes. These are supporting data for the rationale of this neurosteroid as a biomarker and as therapeutic option (ALLO or its synthetic analogues) for PTSD. Taking advantage of the preclinical model of social isolation, that reproduces in adult Swiss mice the behavioral and neuroinflammatory changes that are clinically found in PTSD, our research group has recently shown that this protracted stress condition: (i) induces a systemic proinflammatory profile that negatively affects (ii) the immune/inflammatory aspects of the epididymis, an organ of the male reproductive tract with crucial role for sperm function, and (iii) the quantitative and qualitative sperm parameters. Besides synthesis in the brain, the gonads (ovaries and testis) and peripheral tissues (e.g., adrenal gland), are also potential sites for ALLO production. One hypothesis is that tissular ALLO level is altered with social isolation; these changes, in turn, would be contributing factor to the inflammatory dysregulation in peripheral tissues that occur in response to social isolation. To test this hypothesis, we propose in this project: a) to validate an immunoenzymatic assay for ALLO quantification from both plasma and tissue samples from adult mice, b) to investigate the temporal profile of plasma ALLO levels induced by social isolation; and c) to investigate the temporal profile of ALLO levels present in reproductive and non-reproductive tissues from control (group house) and socially isolated mice; d) to perform histopathological analysis as a readout of the influence of social isolation on tissue histology. The results will help to discover new roles for the role of ALLO in PTSD stress-induced inflammatory physiopathology.