Neuroregulators

埃默里大学西尔维奥·O·孔特精神疾病神经科学中心(CCNMD)0001项目是整个中心不可或缺的组成部分。我们在这个中心的提案中提出了四项研究，这些研究在概念或产生的数据上是相互关联的，并与其他基础和临床项目相关。主要的焦点是早期生活应激导致的神经回路及其功能的改变。简而言之，第一项研究(调查者：Paul M.Plotsky，PhD)利用大鼠新生儿母体分离范例的变化，扩展了我们对发育敏感期和神经回路序列的知识，这些神经回路随着不稳定的早期环境而改变。这些研究将使用行为、神经内分泌 (HPA轴功能)和CNS基因表达为终点。我们试图澄清行为改变、HPA轴改变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，MD，PhD和Paul M.Plotsky，PhD)将通过靶向逆转录病毒介导的大鼠CRF或酪氨酸羟基酶(TH)基因转移，在不同的新生儿时期或成年期间，直接研究早期生活应激导致下丘脑外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，Ph.DI和Paul M.Plotsky，PhD)将通过评估早期生活应激如何改变终纹床核(BNST)的信号平衡来解决重要的功能问题，从而使应激诱导的5-羟色胺输入该区域显示从刺激模式到抑制模式的逆转，从而导致对后续应激源的潜在不适应反应。第四项研究(研究人员：M.Mar Sanchez，PhD和Paul M.Plotsky，PhD)将开始对我们现有队列中的恒河猴大脑样本进行基因表达和受体结合的尸检分析(见Conte Monkey Core 9003)。总而言之，这些成分提供了一项关于早期生活应激对大鼠和恒河猴模型神经回路的长期后果的多方面研究。这些数据对于比较和解释在人体研究中获得的成像数据将是重要的。此外，它们可能具有重要的理论意义和临床意义。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在这个项目和孔特中心的参与者中汇聚在一起，使我们能够以系统的方式解决早期生活应激如何影响选定的神经回路和随后的行为和神经内分泌的问题。

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.