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重点研究NAc（伏隔核）中BDNF（脑源性神经营养因子）的能力 VTA（腹侧被盖区）调节情绪和动机状态。大多数工作在该领域（包括 中心研究人员的大量工作）重点关注 BDNF 的抗抑郁作用 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 赠款），我们为 BDNF 及其信号传导发挥的非常不同的作用提供了新的证据 级联作用于 VTA-NAc 电路级别。这项工作利用了新工具，开发了 与转基因核心结合，能够选择性敲除 VTA 中的 BDNF 信号传导， 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 促抑郁样作用，在该回路中选择性丧失 BDNF，介导抗抑郁样作用 在大鼠和小鼠的几种动物模型中都有效果。 拟议研究的目标是进一步确定 BDNF 在 VTA-NAc 中所发挥的作用，因为它涉及 情绪、动机和抑郁，并开始识别 BDNF 发挥作用的分子底物 产生这些新颖的效果。例如，DNA 表达阵列和行为研究的最新发现 研究表明几种特定的 BDNF 信号蛋白（特别是 PI-3 激酶/Akt 级联） 作为 VTA-NAc 中 BDNF 行为表型的关键介质。我们现在正在系统地分析 这些信号蛋白对抑郁动物模型和抗抑郁作用的影响。我们有 还确定 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，它会因长期暴露于压力而改变，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 的另一个重点。 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 基因表达的控制。我们现在正在使用可用于此的独特分子工具 中心探索这些可能性及其详细的潜在分子机制。