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Early life stress and neurodevelopment: contributions of glucocorticoid plasticity to maturational timing

Grant number: 17/11339-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): October 01, 2017
Effective date (End): August 18, 2018
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Norberto Garcia Cairasco
Grantee:Lívea Dornela Godoy
Supervisor abroad: Kevin Bath
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Brown University, United States  
Associated to the scholarship:14/17959-1 - Characterization of depressive behaviors and morphological aspects involved in early life stress and audiogenic kindling in war strain, BP.DR

Abstract

Adolescence is a developmental period associated with continued organization of neural circuitry regulating emotional behaviors. Recent works have shown that during adolescence suppression of contextual fear retrieval occurs. Rather than a failure to learn the association, in adolescent mice the context was temporarily incapable of eliciting a fear response. The ability to use context to guide reactions to environmental stimuli promotes flexible behavior and the ability to regulate fear responses is critical to emotional resilience and health. Deficits in fear regulation capacity strongly predict vulnerability to an array of affective psychopathology, such as anxiety disorders. Adversities in early life are associated with vulnerability to later psychopathologies in life. Interestingly, early life stress (ELS) experiences can disrupt the Hyporesponsive Stress Period, turning the HPA-axis responsive to stressors. During early postnatal stress, elevated corticosteroid levels coincide with a crucial moment in limbic development. There is growing evidence that brain functioning during development is affected by ELS and can lead to an earlier emergence of the timed developmental suppression of fear behavior. This behavioral outcome is followed by a precocious arrival of Parvalbumin-positive (PV) cells, which was also associated with a specific timed reduction in glucocorticoid (GR) and mineralocorticoid (MR) receptor expression. Thus, in the developing brain, corticosterone may be playing a functional role in both the regulation of timing of cell birth as well as stimulating the onset of circuit maturation process of hippocampus, amygdala and Prelimbic cortex. Our working hypothesis is that a rise in plasma levels of glucocorticoids serves to stimulate the maturation process and that ELS accelerates the onset of glucocorticoid release and signaling to co-ordinate precocious brain and behavioral maturation which will be measured by the development of neurotrophic factors, cellular maturation, and the development of fear-conditioning responses in adolescent mice. We will test those hypotheses using an inhibitor of glucocorticoid synthesis (metyrapone; MET), which will prevent corticosterone elevation, in control and ELS raised animals, blocking adolescence suppression of contextual fear retrieval and maturation at the behavioral and accelerated neural levels, respectively. To evaluate those neurodevelopmental measures, we will use complementary approaches, including neurogenesis, PV cell maturation, and BDNF expression in the BLA and hippocampus.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GODOY, LIVEA DORNELA; ROSSIGNOLI, MATHEUS TEIXEIRA; DELFINO-PEREIRA, POLIANNA; GARCIA-CAIRASCO, NORBERTO; DE LIMA UMEOKA, EDUARDO HENRIQUE. A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications. FRONTIERS IN BEHAVIORAL NEUROSCIENCE, v. 12, JUL 3 2018. Web of Science Citations: 17.
GODOY, LIVEA DORNELA; UMEOKA, EDUARDO H. L.; RIBEIRO, DEIDIANE ELISA; SANTOS, VICTOR RODRIGUES; ANTUNES-RODRIGUES, JOSE; LOURENCO JOCA, SAMIA REGIANE; GARCIA-CAIRASCO, NORBERTO. Multimodal early-life stress induces biological changes associated to psychopathologies. Hormones and Behavior, v. 100, p. 69-80, APR 2018. Web of Science Citations: 3.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.