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Mechanisms underlying the development of hormone-linked adverse behavioural states in females: implications for treatment of premenstrual dysphorias in women

Grant number: 19/05240-6
Support type:Research Grants - Visiting Researcher Grant - International
Duration: January 20, 2020 - March 13, 2020
Field of knowledge:Biological Sciences - Pharmacology
Cooperation agreement: CONFAP ; Newton Fund, with FAPESP as a partner institution in Brazil ; UK Academies
Principal Investigator:Hélio Zangrossi Júnior
Grantee:Hélio Zangrossi Júnior
Visiting researcher: Thelma Lovick
Visiting researcher institution: University of Bristol, England
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The Visiting Researcher (Thelma Lovick) will work with members of the Helio Zangrossi (Principal applicant) and Norberto Coimbra (co-applicant) laboratories. The aim is to facilitate progress on a number of experiments designed to further our understanding of the way that cyclical changes in female sex hormones during the estrous cycle impact on behavior, and the mechanisms that underlie this. Our longer-term goal is to develop new and effective strategies to treat premenstrual disorders in women. A number of experiments are planned: With Zangrossi lab: i) Using a rat model of panic we will test whether short-term administration of low dose of fluoxetine in late diestrus can inhibit the increased susceptibility to panic-like behaviour, which occurs at this stage of the estrous cycle. ii) Whether administration of an analogue of the neuroactive progesterone metabolite allopregnanolone (ALLO) e.g. ganaxolone will have the same effect. iii) Whether stabilising the fluctuation in ALLO concentration during the diestrus phase by blocking conversion from its precursor molecule progesterone e.g. using a 5a-reductase inhibitor, will prevent the panic-like responses in late diestrus. iv) Whether fluoxetine or ganaxolone administration prevents the upregulation of GABAA receptor subunit expression in late diestrus, which is believed to be a main factor underlying the increased excitability in neural circuits that mediate fear-like behaviors. v) To explore the neural substrates that underlie the panic-associated changes observed in females rats submitted to neonatal maternal deprivation. Two projects in the Coimbra lab are designed to complement Zangrossi's work. As fundamental studies of the use of behavioural tests in female rats, they also have broad implications for the scientific community engaged in studies on female brain function. i) Use of a unique naturalistic ethological test (innate fear of rats for snakes) to investigate fear-like behavior of female rats at different stages of their estrous cycle. ii) Consideration of effect of estrous cycle stage of acquisition and recall of fear-like behaviours using commonly used behavioural test of fear and anxiety. Other actions that will add to the impact of the exchange: A new postgraduate course under development will introduce students to sex differences in brain function and drug action. The Visiting Researcher will deliver seminars in English. (AU)