By 2020, people suffering from both major depressive disorder (MDD) and cardiovascular disease (CVD) will be the number one cause of disability (NIMH). The devastating toll MDD and CVD have independently and collectively on human suffering and the economy drives home the fact we need to understand the mechanisms underlying these disorders to reduce their incidence. Dysfunction in the paraventricular nucleus of the hypothalamus (PVN) provides one possible site for mechanisms due to the type of neurons it encompasses. The neurons of the PVN integrate information from multiple brain regions and sample hormone and emotional status to produce an organized output through its various cell types. The PVN also contains a dense matrix of blood vessels compared to surrounding brain. I originally discovered that this density is susceptible to alterations, but theroles of the dense vasculature and the mechanisms for their development are still unknown. This proposal consists of two specific aims testing the hypotheses that increased prenatal glucocorticoids will 1) change the permeability blood-brain barrier through altering its molecular components in vivo and in vitro, and 2) this will result in depressive-like behaviors and alter autonomic function in adulthood. Real time analyses using organotypic brain slices from mice fluorescently expressing GFP under the control of the Tie2 promoter selectively in endothelial cells will help determine if excess glucocorticoids inhibit angiogenesis and increase proteins important for forming the blood-brain barrier. Changes in the neurovascular relationships in the PVN may be an important locus for understanding disorders of the hypothalamic-pituitary-adrenal axis with potential impact for mood disorders and other comorbid disorders including cardiovascular disease. All studies will investigate both male and female mice. This training plan was created jointly by Ms. Frahm and Dr. Tobet and will provide the necessary tools for Ms. Frahm to become an independent scientist.
This proposal tests hypotheses that prenatal stress; through increasing glucocorticoid signaling; will impair the development of the dense vasculature within the paraventricular nucleus of the hypothalamus. Studies will test whether there are long-lasting consequences for physiology and behavior. This proposal will provide critical training that will place the applicant with remarkable potential in an ideal position at the forefront of understanding the immediate and long-term consequences of developmental alterations.