The ability of BDNF in the NAc an VTA in to regulate mood & motivational

项目2主要研究脑源性神经营养因子在伏隔核中的作用。 和VTA(腹侧被盖区)来调节情绪和动机状态。大多数在外地工作(包括 中心研究人员的大量工作)集中在BDNF在脑内的抗抑郁药样影响 海马体或额叶皮质。虽然我们继续分析这些发现的重要性(通过其他 ，我们提供了新的证据，证明了BDNF扮演着非常不同的角色及其信号转导 级联作用于VTA-NAC电路级别。这项工作利用了新的工具，开发了 结合转基因核心，它能够选择性地敲除VTA中的BDNF信号， NAC或其他大脑区域。本研究发现，在VTA-NAC奖赏环路中，BDNF介导 一种促抑郁药样效应，在这个回路中选择性地失去BDNF，介导了一种抗抑郁药样作用 在大鼠和小鼠的几种动物模型中都有明显的效果。 拟议研究的目标是进一步确定BDNF在VTA-NAC中所起的作用 情绪、动机和抑郁，并开始确定BDNF通过哪些分子底物 产生这些新奇的效果。例如，来自DNA表达阵列和行为学的最新发现 研究已经涉及到几个特定的BDNF信号蛋白(特别是PI-3-激酶/Akt级联) 作为VTA-NAC中BDNF行为表型的关键调节因子。我们现在正在系统地分析 这些信号蛋白在抑郁症动物模型和抗抑郁作用中的影响。我们有 也建立了BDNF及其某些信号蛋白作为VTA和VTA形态的关键调节蛋白 我们已经证明，NAC神经元会因慢性应激而改变，我们对此感兴趣 将这些发现与行为联系起来。BDNF和CREB之间的关系是项目2的另一个重点。 我们假设，CREB活性的调节是VTA中BDNF信号的主要功能输出。 NAC途径。相反，我们有越来越多的证据表明，CREB反过来调节VTA-NAC回路 部分通过其对BDNF基因表达的调控来实现。我们现在正在使用独特的分子工具来 中心探索这些可能性及其详细的潜在分子机制。

Project 2 focuses on the ability of BDNF (brain-derived neurotrophic factor) in the NAc (nucleus accumbens) and VTA (ventral tegmental area) to regulate mood and motivational state. Most work in the field (including considerable work by Center investigators) has focused on an antidepressant-like influence of BDNF in hippocampus or frontal cortex. While we continue to analyze the importance of these findings (via other grants), we have provided novel evidence for a very different role played by BDNF and its signaling cascades acting at the level of the VTA-NAc circuit. This work has taken advantage of new tools, developed in conjunction with the Transgenic Core, which enable the selective knockout of BDNF signaling in the VTA, NAc, or other brain regions. This research has revealed that, in the VTA-NAc reward circuit, BDNF mediates a pro-depressant-like effect, with loss of BDNF selectively in this circuit mediating an antidepressant-like effect, in several animal models in both rats and mice. The goal of the proposed studies is to further establish the role played by BDNF in the VTA-NAc as it relates to mood, motivation, and depression, and to begin to identify the molecular substrates through which BDNF produces these novel effects. For example, recent findings from DNA expression arrays and behavioral studies have implicated several specific BDNF signaling proteins (in particular, the PI-3-kinase/Akt cascade) as key mediators of the BDNF behavioral phenotype in the VTA-NAc. We are now systemically analyzing the influence of these signaling proteins in animal models of depression and antidepressant action. We have also established BDNF and certain of its signaling proteins as key regulators of the morphology of VTA and NAc neurons, which we have demonstrated is altered by chronic exposure to stress, and we are interested in relating these findings to behavior. A relationship between BDNF and CREB is another focus of Project 2. We hypothesize that regulation of CREB activity is a major functional output of BDNF signaling in the VTA- NAc pathway. Conversely, we have growing evidence that CREB in turn regulates the VTA-NAc circuit in part via its control of BDNF gene expression. We are now using the unique molecular tools available to this Center to explore these possibilities as well as their detailed underlying molecular mechanisms.