Increased Prenatal Glucocorticoids on Vascularization in the Paraventricular Nucl

描述（由申请人提供）：到2020年，患有重度抑郁症（MDD）和心血管疾病（CVD）的人将成为残疾（NIMH）的头号原因。MDD和CVD对人类痛苦的独立和集体的破坏性代价，经济推动了我们需要了解这些疾病背后的机制以减少其发病率的事实。下丘脑室旁核（PVN）的功能障碍提供了一个可能的机制，由于它所包含的神经元类型的网站。PVN的神经元整合来自多个大脑区域的信息，并对激素和情绪状态进行采样，以通过其各种细胞类型产生有组织的输出。与周围的大脑相比，PVN还包含密集的血管基质。我最初发现这种密度容易改变，但 致密脉管系统的作用及其发育机制仍不清楚。该提案包括两个具体目标，以验证以下假设：产前糖皮质激素增加将1）通过改变体内和体外的分子组成来改变血脑屏障的通透性，以及2）这将导致抑郁样行为并改变成年后的自主神经功能。使用来自在内皮细胞中选择性地在Tie 2启动子控制下荧光表达GFP的小鼠的器官型脑切片的真实的时间分析将有助于确定过量的糖皮质激素是否抑制血管生成并增加对于形成血脑屏障重要的蛋白质。PVN中神经血管关系的变化可能是了解下丘脑-垂体-肾上腺轴疾病的重要位点，对情绪障碍和其他共病疾病（包括心血管疾病）具有潜在影响。所有研究将研究雄性和雌性小鼠。该培训计划由Frahm女士和Tobet博士共同制定，将为Frahm女士成为独立科学家提供必要的工具。

DESCRIPTION (provided by applicant): 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 the roles 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.