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

NAc 和 VTA 中的 BDNF 调节情绪的能力

• 批准号: 8114142
• 负责人: Luis Fernando Parada
• 金额: $ 16.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114142
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animal Model; Antidepressive Agents; Behavior; Behavioral; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Cells; Chronic; DNA; Exposure to; Gene Expression; Gene Transfer; Goals; Grant; Hippocampus (Brain); Knock-out; Knockout Mice; Mediating; Mediator of activation protein; Mental Depression; Molecular; Moods; Morphology; Motivation; Mus; Neurons; Nucleus Accumbens; Output; Pathway interactions; Phenotype; Play; Rattus; Regulation; Research; Research Personnel; Rewards; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Transgenic Organisms; Ventral Tegmental Area; Viral; Work; frontal lobe; interest; mood regulation; novel; tool

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.

项目2的重点是BDNF（脑源性神经营养因子）在NAc（脑桥核）中的能力 腹侧被盖区（ventral tegmental area，VTA）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在脑内的抗抑郁样影响上。 海马体或额叶皮层。虽然我们继续分析这些发现的重要性（通过其他 我们为BDNF及其信号传导所起的非常不同的作用提供了新的证据 级联作用于VTA-NAc电路的水平。这项工作利用了新的工具， 与能够选择性敲除VTA中BDNF信号传导的转基因核心结合， NAc或其他大脑区域。这项研究表明，在VTA-NAc奖励回路中，BDNF介导了 一种类似促抑郁症的效应，在这个回路中选择性地失去BDNF，介导一种类似抗抑郁症的效应。 在大鼠和小鼠的几种动物模型中， 这项研究的目的是进一步确定BDNF在VTA-NAc中的作用， 情绪、动机和抑郁，并开始识别脑源性神经营养因子通过的分子底物 产生了这些新奇的效果。例如，最近从DNA表达阵列和行为分析中发现， 研究已经涉及几种特定的BDNF信号传导蛋白（特别是PI-3-激酶/Akt级联） 作为VTA-NAc中BDNF行为表型的关键介质。我们现在正在系统地分析 这些信号蛋白在抑郁症和抗抑郁作用的动物模型中的影响。我们有 还确立了BDNF及其某些信号蛋白作为VTA形态的关键调节因子， NAc神经元，我们已经证明了慢性暴露于压力会改变，我们感兴趣的是 将这些发现与行为联系起来。BDNF和CREB之间的关系是项目2的另一个焦点。 我们假设CREB活性的调节是VTA中BDNF信号传导的主要功能输出， 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。我们现在正在使用独特的分子工具， 中心探索这些可能性以及它们详细的潜在分子机制。