Neuroregulators

神经调节剂

• 批准号: 6850627
• 负责人: PAUL M PLOTSKY
• 金额: $ 15.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850627
• 关键词: Macaca mulatta; age difference; behavioral /social science research tag; corticotropin releasing factor; developmental neurobiology; developmental psychology; disease /disorder proneness /risk; early experience; environmental stressor; gender difference; hormone receptor; hypothalamic pituitary adrenal axis; laboratory rat; major depression; mother deprivation; neural plasticity; neuroanatomy; neuroendocrine system; neuroregulation; psychological stressor; stress

Project 0001 of the Emory University Silvio O. Conte Center for the Neuroscience of Mental Disorders (CCNMD) represents an integral component of the overall Center. We have proposed four studies that in concept or data generated are interrelated to one another and to other basic and clinical projects in this Center proposal. The primary focus is on early life stress induced alterations in neurocircuits and their function. Briefly, the first study (Investigator: Paul M. Plotsky, PhD) extends our knowledge of sensitive periods in development and the sequence of neurocircuits that change in response to an unstable early environment using variations on the rat neonatal maternal separation paradigm. The studies will use behavioral, neuroendocrine (HPA axis function) and CNS gene expression as endpoints. We seek to clarify the relationship between behavioral alterations, HPA axis changes, and adaptations of other central circuits. The second study (Investigators: Kerry Ressler, MD, PhD, & Paul M. Plotsky, PhD) will directly address the role of early life stress induced up-regulation of extra-hypothalamic CRF systems and the locus coeruleus NE system using targeted retrovirus-mediated gene transfer of the rat CRF or tyrosine hydroxylase (TH) genes during different neonatal periods or in adulthood. The third study (Investigators: Donald Rainnie, Ph.DI, & Paul M. Plotsky, PhD)will address important functional issues by assessing how early life stress may alter the balance of signaling in the bed nucleus of the stria terminalis (BNST) such that stress-induced 5-HT input to this region shows a reversal from a stimulatory to inhibitory pattern resulting in a potentially maladaptive response to subsequent stressors. The fourth study (Investigators: M. Mar Sanchez, PhD, & Paul M. Plotsky, PhD) will begin postmortem analyses of gene expression and receptor binding in a sampling of rhesus monkey brains from our existing cohorts (see Conte Monkey Core 9003). Together, these components provide a multifaceted investigation of the long-term consequences of early life stress on neurocircuits in the rat and rhesus models. These data will be important for comparison and interpretation of imaging data obtained in the human studies. Furthermore, they may hold important theoretical implications and clinical relevance. The convergence of excellent animal models, sophisticated scientific questions, cutting edge techniques, and extraordinary expertise among the participants of this project and the Conte Center permit us to address the question of how early life stress affects selected neurocircuits and subsequent behavioral and neuroendocrine in a systematic way.

埃默里大学 Silvio O. Conte 精神障碍神经科学中心 (CCNMD) 的 0001 项目是整个中心的一个组成部分。我们提出了四项研究，这些研究在概念或生成的数据上相互关联，并且与该中心提案中的其他基础和临床项目相互关联。主要焦点是早期生活压力引起的神经回路及其功能的改变。简而言之，第一项研究（研究者：Paul M. Plotsky 博士）利用大鼠新生儿母体分离范式的变化，扩展了我们对发育敏感期以及响应不稳定的早期环境而变化的神经回路序列的了解。这些研究将使用行为、神经内分泌 （HPA 轴函数）和 CNS 基因表达作为终点。我们试图阐明行为改变、HPA 轴变化和其他中枢回路适应之间的关系。 第二项研究（研究人员：Kerry Ressler，医学博士、哲学博士和 Paul M. Plotsky 博士）将通过在不同的新生儿期或成年期对大鼠 CRF 或酪氨酸羟化酶 (TH) 基因进行靶向逆转录病毒介导的基因转移，直接解决早期生活压力诱导的下丘脑外 CRF 系统和蓝斑 NE 系统上调的作用。 第三项研究（研究人员：Donald Rainnie 博士和 Paul M. Plotsky 博士）将通过评估早期生活压力如何改变终纹床核 (BNST) 的信号平衡来解决重要的功能问题，从而使压力诱导的 5-HT 输入到该区域显示出从刺激模式到抑制模式的逆转，从而导致对后续压力源的潜在适应不良反应。第四项研究（研究人员：M. Mar Sanchez 博士和 Paul M. Plotsky 博士）将开始对我们现有队列中恒河猴大脑样本的基因表达和受体结合进行尸检分析（参见 Conte Monkey Core 9003）。这些组件共同提供了对早期生活压力对大鼠和恒河猴模型神经回路的长期影响的多方面研究。这些数据对于比较和解释人类研究中获得的成像数据非常重要。此外，它们可能具有重要的理论意义和临床意义。该项目和孔特中心的参与者融合了优秀的动物模型、复杂的科学问题、尖端技术和非凡的专业知识，使我们能够系统地解决早期生活压力如何影响选定的神经回路以及随后的行为和神经内分泌的问题。