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Current Research Projects

In this integrated translational project, scientists from basic and clinical fields address the question of why women are at twice the risk for MDD than men. We hypothesize that sex differences in MDD are initiated during fetal development, during hypothalamic-pituitary-adrenal (HPA) circuitry development and the sexual differentiation of the brain, and a period in which fetal risk factors for MDD have been identified.

The overarching goal is to test hypotheses regarding the roles of adrenal and gonadal signaling pathways regulating brain-derived nerve growth factor (BDNF; associated with MDD) and its interactions with gamma aminobutyric acid (GABA)-ergic, glutamate (GLU)-tamatergic and nitric oxide (NO) mechanisms in development of key brain regions in stress response circuitry. Research projects include one human study (Project 1), and two animal studies (Projects 2 and 3).

Project 1: Genes & Hormonal Fetal Antecedents to Sex Differences in the Brain in Depression
This project investigates the relationships between maternal-fetal stress, hormones, genes, and structural and functional brain abnormalities seen in women and men diagnosed with Major Depressive Disorder (MDD). Specifically, it will examine the sex differences in associations between abnormal maternal-fetal hypothalamic-pituitary-adrenal (HPA) environment, genetic polymorphisms in HPA (or stress response) circuitry development, and adult function.

Project 2: Animal Models of Sex-Specific HPA Axis Development
This project focuses on the early development of HPA axis nuclei and uses genetic knock-out strategies in mice to differentiate genetic from hormonal influences on sex differences in HPA morphological development.

Project 3: Sex-Specific Programming of the HPA Axis by Glucocorticoids
This project uses a fetal glucocorticoid exposure model in rats to identify mechanisms that establish sex differences in developing HPA circuitry. Projects 2 and 3 both relate their results to the potential impact on sex differences in adult HPA hormonal dysregulation and adult depressive-like phenotypic behavior and comorbidity with cardiovascular dysregulation or metabolic syndrome.

Translational Aspects of Our Research

The research will identify sex differences in potential brain abnormalities in association with hormonal dysregulation in HPA and HPG axes to characterize sex differences in adult MDD. The focus of both human and animal model studies lies in the timing of fetal and genetic risk factors associated with sex differences in MDD. Project 1 examines the adult brain and HPA circuitry functioning in humans and will identify genetic and prenatal hormonal and immunologic risk factors for understanding sex differences in brain abnormalities associated with MDD. Projects 2 and 3 characterize genetic versus hormonal developmental mechanisms for understanding the human results in key regions in HPA circuitry. Based on our existing data and the need to examine multiple mechanisms, the animal studies will focus somewhat selectively on the hypothalamic paraventicular nucleus (PVN) as the key output site of the HPA axis. However, based on the need to consider the extended circuitry of the HPA axis, results in the PVN will be contrasted whenever possible to those in the ventromedial hypothalamic nucleus (VMN) and hippocampus, which will contribute importantly to understanding of the development of sex differences in MDD.

Animal models in Projects 2 and 3 will be used to test molecular bases for alterations in the development of the HPA axis in the context of genetic sex and hormonal influences. Furthermore, animal models will provide for tests of adult functional consequences associated with these developmental alterations and with adult MDD phenotypic behavior and endocrine status. Thus, Project 1 in humans will inform Projects 2 and 3 in animals by indicating the relative involvement of each component of the HPA axis in MDD from the perspective of developmental and adult sex differences.