NEUROTROPIC DRUGS, HORMONES, AND BRAIN FUNCTION

神经营养药物、激素和脑功能

• 批准号: 2243000
• 负责人: SAUL M SCHANBERG
• 金额: $ 21.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-09-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2243000
• 关键词: biological signal transduction; developmental neurobiology; developmental nutrition; endorphins; environmental adaptation; enzyme induction /repression; gene expression; hormone regulation /control mechanism; in situ hybridization; insulin; laboratory rat; mother deprivation; neuroendocrine system; neuropharmacology; newborn animals; northern blottings; nutrient interaction; nutrition related tag; opioid receptor; ornithine decarboxylase; protooncogene; regulatory gene; serotonin; somatotropin; touch

Development in mammals is profoundly affected by environmental stimuli. Physical stimuli provided by the mother appear to be most critical for survival and growth. The consequences of disrupting this interaction range from marked suppression of certain neuroendocrine and physiological systems following short periods of separation to retardation of growth and behavioral development during long-term separation. These effects are the result of individual cues from the mother which trigger specific developmental adaptations in the infant. Fundamental questions remain as to the biological nature of this mother-infant interaction. The long-term objective of this laboratory is to understand the neonatal pathophysiology of maternal separation (MS). The current goals are to determine how two key consequences of short-term MS, loss of tactile stimulation (MTD) and food deprivation (MFD) affect neonatal development. The adaptive cellular changes evoked by MTD are organized and initiated by the CNS while the changes caused by MFD are due to the direct regulatory actions of D- glucose on neonatal hepatocyte metabolism. Studies are targeted to elucidate the biochemical and molecular mechanisms mediating the specific alterations in cell function resulting from either MTD or short-term MFD. The specific aims are: (1) to further our understanding of beta-endorphin (betaE) as the prime CNS organizer of the adaptive response in the neonate to MTD. Specifically, to investigate whether CNS betaE itself is the mediator of MTD and whether the effects of MTD or CNS administered betaE on ornithine decarboxylase (ODC) expression occur through CNS epsilon receptors, while those on DNA synthesis and insulin catabolism are mediated by classical opioid receptors, (2) to determine the mechanisms by which MTD suppresses GH secretion normally evoked by serotonin (5-HT). Specifically, we will study the function of 5-HT neurons and receptor subtypes by measuring 5-HIAA accumulation and GH secretion evoked by specific serotoninergic receptor agonists/antagonists during MTD paradigms, and (3) to test the hypothesis that the inhibition of hepatic ODC expression in the preweanling by both MTD and MFD is mediated via a down-regulation of intracellular signal transduction systems. Initial studies will focus on the expression of the immediate early genes c-fos, c-jun and c-myc. The experimental approach is to assess multiple growth-related parameters in developing organs and then to use these measurements as indices of altered functional maturation of these tissues resulting from MTD or MFD. Biological systems studied include: molecular (synthesis of DNA, phosphoinositide and cAMP, and expression of ODC and the proto-oncogenes c-fos, c-jun and c-myc), endocrine (GH, insulin, prolactin and corticosterone), neurotransmitters (5-HT and catecholamines), and opioids (beta-endorphin, dynorphin and enkephalins). Studies to date have clearly established that the rat pup model of maternal deprivation is a productive and important paradigm for investigating the relationship between maternal-infant behavioral patterns and neonatal development, and the consequences of disrupting this interaction as occurs in very premature and in non-organic failure-to- thrive human infants.

哺乳动物的发育受到环境刺激的深刻影响。 母亲提供的身体刺激似乎对 生存和成长。 破坏这种互动的后果 从某些神经内分泌和生理学的明显抑制范围 在短期间分离以延迟增长和 长期分离期间的行为发展。 这些影响是 母亲的个人提示的结果，触发特定的 婴儿的发育适应。 基本问题仍然是 具有这种母亲相互作用的生物学性质。 长期 该实验室的目的是了解新生儿病理生理学 孕产妇分离（MS）。 当前的目标是确定两个 短期MS的关键后果，触觉刺激的丧失（MTD）和 粮食剥夺（MFD）影响新生儿发展。 自适应细胞 MTD引起的变化是由中枢神经系统组织和发起的 由MFD引起的变化是由于D-的直接调节作用 新生儿肝细胞代谢上的葡萄糖。 研究针对 阐明介导特异性的生化和分子机制 由MTD或短期MFD产生的细胞功能改变。 具体目的是：（1）进一步了解β-内啡肽 （betae）作为新生儿自适应反应的主要中枢神经系统组织者 到MTD。 具体来说，调查中枢神经系统本身是否是 MTD的介体以及MTD或CNS的影响 鸟氨酸脱羧酶（ODC）表达通过CNS Epsilon发生 受体，而DNA合成和胰岛素分解代谢的受体是 由经典阿片类药物受体介导，（2）确定 MTD抑制了通常被5-羟色胺（5-HT）引起的GH分泌。 具体而言，我们将研究5-HT神经元和受体的功能 亚型通过测量5-HIAA的积累和GH分泌。 MTD期间特定的5-羟色胺能受体激动剂/拮抗剂 范式和（3）测试抑制肝的假设 MTD和MFD预先断层中的ODC表达都是通过A介导的 细胞内信号转导系统的下调。 最初的 研究将侧重于直接早期基因C-FOS的表达， C-Jun和C-Myc。 实验方法是评估多个与生长有关的参数 在开发器官，然后使用这些测量值作为指标 由MTD或MFD引起的这些组织的功能成熟改变。 研究的生物系统包括：分子（DNA的合成， 磷酸肌醇和cAMP，以及ODC和原始基因的表达 C-FOS，C-JUN和C-MYC），内分泌（GH，胰岛素，催乳素和 皮质酮），神经递质（5-HT和Catecholamines）和阿片类药物 （β-内啡肽，Dynorphin和Enkephalins）。 迄今为止的研究清楚地确定了大鼠幼犬模型 孕产妇的剥夺是一个富有成效且重要的范式 研究产妇侵害行为模式之间的关系 和新生儿的发展以及破坏这一点的后果 相互作用是非常过早的和非有机故障的相互作用 - 繁荣的人类婴儿。