In utero programming of CRF neurons by glucocorticoids

糖皮质激素对 CRF 神经元的子宫内编程

• 批准号: 7585660
• 负责人: DEAN MYERS
• 金额: $ 24.31万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585660
• 关键词: Accounting; Address; Adrenal Glands; Adrenalectomy; Adult; Age; Amygdaloid structure; Animals; Anterior Pituitary Gland; Anxiety; Automobile Driving; Barker Hypothesis; Behavior; Behavioral; Betamethasone; Blood - brain barrier anatomy; Cardiovascular Diseases; Cell Nucleus; Clinical; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Development; Disease; Dyslipidemias; Epidemiology; Epigenetic Process; Estrous Cycle; Event; Exhibits; Exposure to; Female; Fetus; Fright; Functional disorder; Future; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Glucose Intolerance; High Risk Woman; Hippocampus (Brain); Hyperactive behavior; Hyperglycemia; Hypertension; Individual; Insulin Resistance; Intervention; Laboratories; Medial; Mediator of activation protein; Messenger RNA; Metabolic Diseases; Metabolic Syndrome X; Mineralocorticoid Receptor; Molecular; Neurons; Neuropeptides; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Peptides; Perinatal Exposure; Phenotype; Physiological; Pituitary Gland; Pituitary-Adrenal System; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Premature Labor; Principal Investigator; Production; RU-486; Rattus; Role; Site; Staging; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Syndrome; Time; Variant; antalarmin; clinical practice; clinically relevant; embryo/fetus; experience; exposed human population; fetal programming; high risk; in utero; indexing; male; maternal stress; neuron development; offspring; paraventricular nucleus; parvocellular; pregnant; programs; response; theories; tool

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.

描述（由申请人提供）：安装证据支持以下理论：在妊娠关键窗口期间，发育中的胎儿不合时宜地暴露于糖皮质激素（GC）会导致获得行为，神经内分泌和生理障碍成年人的行为，成年后的行为性疾病。这种现象被称为“胎儿编程”。通常将合成GC用于怀孕的妇女，其早产和分娩风险很高。由合成GC引起的后代中的疾病包括下丘脑 - 垂体 - 肾上腺（HPA）轴的干扰，恐惧/焦虑，代谢性疾病和高血压的改变。由于成人的GC产生过多可促进高血压，高血糖/胰岛素抵抗和血脂异常，因此增加HPA功能和相关行为的发育节目在这些疾病的建立中可能是不可或缺的。在暴露于子宫内合成GC的后代中，杏仁核（CEA）的中央核和下丘脑旁脑膜间核（PVN）的表达均增加了皮质激素释放因子（CRF）的表达。 CRF是调节前垂体ACTH分泌的主要神经肽，也是恐惧/焦虑的主要调节剂。我们提出，PVN和CEA中的编程CRF神经元的发育和表达在GC编程的过度HPA活性和高焦虑表型中至关重要。 AIM 1将确定孕产妇的合成GC的递送是否增加了CRF表达和PVN和CEA中CRF神经元的数量，并确定表达增加的开始时间以及易感性的发育窗口。 AIM 2将确定MPPVN中的AVP表达是否是通过孕妇的合成糖皮质激素来编程的。 AIM 3 DIDECLTY检查了CRF在编程恐惧/焦虑中的作用以及HPA轴的功能增加，以响应子宫对母体施用的合成糖皮质激素的暴露。 AIM 3还将评估BNST与Amgydala作为CRF行动所在的恐惧/焦虑编程中的作用。 AIM 4将确定杏仁核的GC刺激对于维持CEA和PVN中CRF表达增加，焦虑/恐惧的增加以及HPA功能的增加是否至关重要。