Project 5-CREB and the other targets in Projects 1-4 in reward regions in depress

我们中心最近发起了一项新的倡议，以研究CREB和其他感兴趣的分子靶标 在尸检中抑郁的人的大脑奖赏区域投射1-4个。这项工作主要集中在 伏隔核(NAC)和腹侧被盖区(VTA)。这一努力代表着一个新的项目5 中锋在这场竞争性的更新中。 我们已经开始通过达拉斯大脑收藏中心收集抑郁症患者的大脑。 这样的收集一直在快速进行，这确保了足够大的 足够的样本进行有意义的分析。该项目为中心的研究提供了几个强大的功能。1) 我们使用最严格和最严格的脑组织质量测量方法，这对尸检是必不可少的。 大脑研究。2)我们对人脑奖励区域的关注是对该领域当前大多数努力的补充， 在很大程度上分析了其他大脑回路。3)通过关注相同的基因和蛋白质 临床前研究人员在抑郁症啮齿动物模型中进行研究，该项目为 我们中心的关键翻译任务。4)我们将研究这些分子靶标作为函数 抑郁症的诊断(即，在患有重度抑郁症的患者中可见)以及作为症状的函数 抑郁症(即，在几种诊断中可以看到，包括重度抑郁症、躁郁症和 分裂情感障碍伴抑郁)。5)VTA和NAC分子靶点的改变也将是 以抑郁症的发育风险因素为特征的(基于广泛的 人类受试者)，以及最近被认为与抑郁症遗传风险有关的特定基因类型。6)项目 将研究长期抗抑郁药物治疗对这些分子靶点的可能影响。 用原型制剂治疗6个月的啮齿动物。 我们对这一新倡议的潜力感到非常兴奋。我们已经论证了研究的可行性 在人类死后NAC中感兴趣的各种基因产物，并已经记录 其中一些产品的异常，我们知道在啮齿动物抑郁模型中会发生改变。在 与此同时，来自人体组织的发现为这些分子的调控提供了新的见解 路径，这是指导其他项目的临床前研究。此外，我们还建立了 对人类死后组织进行高级分子分析的能力，包括远远超出 传统的DNA表达阵列、染色质免疫沉淀(CHIP)、芯片上的芯片和微RNA 结合染色质和基因调控核心进行检测。总而言之，拟议的研究将 为人类VTA-NAC相关的分子病理学提供独一无二的强大分析 抑郁症及其治疗。

Our Center has recently launched a new initiative to study CREB and the other molecular targets of interest to Projects 1-4 in brain reward regions of depressed humans on autopsy. This work focuses primarily on the NAc (nucleus accumbens) and VTA (ventraltegmental area). This endeavor represents a new Project 5 for the Center in this competitive renewal. We have already begun the collection of brains from depressed humans via the Dallas Brain Collection. Such collections have been proceeding at a rapid pace, which ensures the availability of an adequately large enough sample for meaningful analysis. The Project offers several powerful features for Center research. 1) We utilize the most stringent and rigorous measures of brain tissue quality, which is essential for postmortem brain studies. 2) Our focus on human brain reward regions complements most current efforts in the field, which have largely analyzed other brain circuits. 3) By focusing on the same genes and proteins that preclinical investigators study in rodent models of depression, the Project provides a major driving force for the critical translational mission of our Center. 4) We will examine these molecular targets both as a function of a diagnosis of depression (i.e., as seen in patients with major depression) and as a function of symptoms of depression (i.e., as seen across several diagnoses, including major depression, bipolar depression, and schizoaffective disorder with depression). 5) Alterations in molecular targets in the VTA and NAc will also be characterized as a function of developmental risk factors for depression (based on extensive history of the human subjects) and of particular genotypes recently implicated in genetic risk for depression. 6) The Project will study the possible influence of long-term antidepressant treatment on these molecular targets by treating rodents with prototypical agents for 6 months. We are very excited by the potential of this new initiative. We have demonstrated the feasibility of studying the various gene products of interest in human postmortem NAc and have already documented abnormalities in some of these products, which we know are altered in rodent depression models. At the same time, findings from the human tissue have provided new insight into regulation of these molecular pathways, which is guiding the preclinical research in the other Projects. Moreover, we have established the capability of carrying out advanced molecular analyses on human postmortem tissue, including, well beyond traditional DNA expression arrays, chromatin immunoprecipitation (ChIP), ChIP on chip, and microRNA assays in conjunction with the Chromatin and Gene Regulation Core. Together, the proposed studies will provide a uniquely powerful analysis of molecular pathologies in the human VTA-NAc associated with depression and its treatment.