Expression, behavioral effects and fertility parameters of beta-defensins and neuropeptide Y in a mouse model of post-traumatic stress disorder (PTSD) related to neurosteroids profile

• Grant number: 14/19378-6
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2015 - August 31, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Maria Christina Werneck de Avellar
• Grantee: Maria Christina Werneck de Avellar
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Antonio de Miranda ; Cristoforo Scavone ; Graziano Pinna
• Associated grant(s): 15/50011-4 - Defining the relationship between sex hormones, protein quality control and male fertility, AP.R SPRINT

Abstract

Stress has profound effects on emotional and sexual behavior by affecting hormonal responses. People exposed to stress develop a number of affective disorders, including post-traumatic stress disorder (PTSD), a debilitating condition frequently comorbid with other psychiatric illness, sexual dysfunction, and impaired functioning. The basolateral amygdala, critical to emotional behavior, is modulated by the neurosteroid allopregnanolone (Allo), a GABAA receptor positive modulator. Allo, synthesized in the brain by 5-alpha-reductase (5-alpha-RI), is deficient in anxious humans and in PTSD animal model, including the socially isolated (SI) mouse. In SI mice a decrease of corticolimbic 5-alpha-RI expression may also result in decreased levels of testosterone's metabolites, including 5±-DHT. However, the neural target involved in this neurosteroid downregulation remains unknown. Neuropeptide Y (NPY) and beta-defensins (BDs) are androgen-dependent antimicrobial proteins expressed in the brain and in male reproductive tissues. NPY presents an anti-stress and anxiolytic role, but its regulation in PTSD remains unexplored. BDs are highly expressed in the epididymis and affect sperm function. Their relation with neurosteroids or role on emotions has never been investigated. This proof-of-concept study is a critical, basic science, translational first step investigation that will focus on: a) the relation of steroids and neurosteroids biosynthesis in the central nervous system (corticolimbic areas) with BD (SPAG11C) and NPY expression during protracted stress in the SI mice model; b) the comparison of the behavioral effects of BD with the role of NPY in the modulation of emotional behavior that involves neurosteroids and the GABAergic system, and c) on the peripheral role of neuroactive steroids and BD and NPY expression in the epididymis during social isolation stress and their impact on sperm parameters. RT-qPCR, Western blot, immunohistochesmitry and GC-MS/LC-MS methodologies will be used. The results may open a new avenue in the search for novel anxiolytic drugs for PTSD and other anxiety disorders, unveil new biomarkers for these conditions, as well as shed light into the effects of stress on pathophysiology of epididymis and reproduction. (AU)