In utero programming of CRF neurons by glucocorticoids

描述(由申请人提供)：越来越多的证据支持这样的理论，即发育中的胎儿在怀孕的关键时期不适当和/或过度暴露于糖皮质激素(GC)会导致成年后获得行为、神经内分泌和生理障碍。这种现象被称为“胎儿编程”。合成GC通常用于早产和分娩的高危孕妇。合成GC引起的后代疾病包括下丘脑-垂体-肾上腺(HPA)轴紊乱、恐惧/焦虑改变、代谢障碍和高血压。由于成人过量的GC产生会促进高血压、高血糖/胰岛素抵抗和血脂异常，因此HPA功能和相关行为的发育编程在这些疾病的建立中可能是不可或缺的。在宫内暴露于人工合成GCs的子代中，成年后促肾上腺皮质激素释放因子(CRF)在杏仁中央核(CEA)和下丘脑室旁核(PVN)的表达都增加。CRF是调节垂体前叶ACTH分泌的主要神经肽，也是恐惧/焦虑的主要调节器。我们认为，编程CRF神经元在PVN和CEA的发育和表达是GC编程的HPA过度活动和高度焦虑表型的核心。目的1确定人工合成的GC是否会增加CRF的表达，以及PVN和CEA中CRF神经元的数量，并确定表达开始增加的时间以及发育的易感性窗口。目标2将确定mpPVN中AVP的表达是否通过母体给药合成糖皮质激素来编程。目的3直接研究CRF在编程恐惧/焦虑中的作用，以及宫内暴露于母体给药合成糖皮质激素后HPA轴功能的增强。AIM 3还将评估BNST与Amgydala作为CRF活动场所在恐惧/焦虑编程中的作用。目的4将确定杏仁核的GC刺激是否对接受合成GC的妊娠大鼠的子代维持CEA和PVN中CRF表达的增加、焦虑/恐惧的增加和HPA功能的增强是必要的。

DESCRIPTION (provided by applicant): Mounting evidence supports the theory that inopportune and/or excessive exposure of a developing fetus to glucocorticoids (GCs) during critical windows of gestation results in the acquisition of behavioral, neuroendocrine and physiological disorders as adults. This phenomenon has been referred to as "fetal programming". Synthetic GCs are routinely administered to pregnancy women at high risk for preterm labor and delivery. Disorders in the offspring arising from synthetic GCs include disturbances of the hypothalamo-pituitary-adrenal (HPA) axis, altered fear/anxiety, metabolic disorders and hypertension. Since excessive GC production in adults promotes hypertension, hyperglycemia/insulin resistance and dyslipidemia, developmental programming of increased HPA function and related behaviors is potentially integral in the establishment of these disorders. In offspring exposed to synthetic GCs in utero, expression of corticotropin releasing factor (CRF) is increased in both the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN) at adulthood. CRF is the primary neuropeptide regulating anterior pituitary ACTH secretion, and a major modulator of fear/anxiety. We propose that programming CRF neuron development and expression in the PVN and CeA is central in the GC-programmed excessive HPA activity and high anxiety phenotype. AIM 1 will determine if maternal delivery of synthetic GCs increases both CRF expression and the number of CRF neurons in the PVN and CeA and determine the timing of the onset of increased expression as well as the developmental window of susceptibility. AIM 2 will determine if AVP expression in the mpPVN is programmed via maternal administration of synthetic glucocorticoids. AIM 3 direclty examines the role of CRF in programming fear/anxiety and the increased function of the HPA axis in response to in utero exposure to maternally administered synthetic glucocorticoids. Aim 3 will also assess the role of the BNST vs. amgydala as the site of CRF action in the programming of fear/anxiety. AIM 4 will determine if GC stimulation of the amygdala is essential for maintaining increased CRF expression in the CeA and PVN, increased anxiety/fear and increased HPA function in the offspring of pregnant rats which received synthetic GCs.