Impact of inhibiting cerebellar prostaglandin or estradiol production during the second postnatal week on later microglia activation state

• Grant number: 17/23356-6
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: January 01, 2019
• End date: April 30, 2019
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Arielle Cristina Arena
• Grantee: Andressa Rejani Ribeiro Leite
• Supervisor: Margaret Merryl McCarthy
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Institution abroad: University of Maryland, Baltimore (UMB), United States
• Associated to the scholarship: 17/03997-7 - Influence of in utero and lactacional exposure to the anti-inflammatory ibuprofen: late repercussion on male reproductive parameters in rats, BP.IC

Abstract

Microglia is emerging as important regulators of brain development. This cell responds and produces prostaglandin E2 (PGE2), creating a feedback loop. PGE2 is related to inflammation, and early-onset neural inflammation is a leading environmental risk for some disorders. Microglia has a "semi-activation" peak during the second post-natal week in healthy cerebellum. Cerebellar development involves an intrinsic gene expression profile that creates a vulnerability to inflammation deregulation. In the healthy cerebellum, PGE2 stimulates the aromatase enzyme leading to increased estradiol production and the regulation of growth of Purkinje neurons. The second postnatal week is a sensitive period and the disturbance of this pathway during this period impairs the development of the Purkinje neuron and results in long-term behavioral deficits revealed by social gambling, cognition, and somatosensory thresholds. Thus, the goal of this study is to understand the natural progression of microglial transformation in the cerebellum and the role that PGE2 and E2 play in that progression. For this, male and female pups will receive injections of inhibitors of COX (Indomethacin, 0.5 ug/ul), aromatase (Formestane, 1.0 ug/ul) or both directly into the cerebellum on PN 8 & 10 and euthanized on PN11 or on PN17. Brains will be collected and cerebellums processed for immunohistochemical identification of microglia by Iba1 staining followed by morphological categorization. Additional sections will be used for staining of markers of activated microglia, such as arginase and mannose. The results of this study will provide important insight into the endogenous regulators of microglia activational state in the cerebellum. (AU)