The ability of the transcription factor CREB in the Nac to regulate mood

Nac中转录因子CREB调节情绪的能力

• 批准号: 7333042
• 负责人: RONALD S. DUMAN
• 金额: $ 23.66万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333042
• 关键词: Acute; Affective; Animal Model; Animals; Antidepressive Agents; Behavior; Behavioral; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Candidate Disease Gene; Cholecystokinin; Chronic; Complex; Condition; DNA; Data; Dynorphins; Emotional; Gene Targeting; Genes; Glutamate Receptor; Grant; Human; Knockout Mice; Mediating; Mental Depression; Molecular; Moods; Neurons; Nucleus Accumbens; Opioid Peptide; Pathway interactions; Phenotype; Protein Family; Range; Regulation; Rewards; Role; Role playing therapy; Social isolation; Stimulus; Stress; Symptoms; Ventral Tegmental Area; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; chromatin immunoprecipitation; chromatin remodeling; emotional stimulus; hedonic; mood regulation; promoter; response; transcription factor

Project 1 focuses on the ability of the transcription factor CREB in the NAc (nucleus accumbens) to regulate mood and motivational state. We have considerable evidence that increased CREB function in this brain region, which occurs under several conditions of active stress, causes a decrease in an animal's sensitivity to emotional stimuli, regardless of whether the stimulus is aversive or rewarding. Conversely, reduced CREB function, caused by a lack of emotional stimulation (e.g., prolonged social isolation), has the opposite effect. These findings suggest that CREB in the NAc may function as a key molecular gate between emotional stimuli and their behavioral responses. A possible relationship between both extremes in CREB activity and the different range of symptoms seen in various subtypes of human depression will be further explored in animal models. Preliminary data, for example, show that either extreme change in CREB activity in the NAc (either excessively high or excessively low activity), and its behavioral consequences, can be corrected by chronic, not acute, antidepressant treatment. Related studies will characterize target genes through which CREB produces this behavioral phenotype in the NAc. The genes encoding the opioid peptide dynorphin and the AMPA glutamate receptor subunit GluR1 are examples of such targets of CREB that will be examined in this Project, as will additional targets identified with DNA expression arrays and ChIP on chip (chromatin immunoprecipitation x promoter) arrays. ChIP will also be used to characterize the molecular mechanisms by which CREB, at the level of chromatin remodeling, regulates its target genes. In addition, the Project will investigate the role played by CREB in the VTA (ventral tegmental area) in regulating depression-like behavior, as well as establish the behavioral phenotype of several other CREB family proteins, which we have shown recently subserve very different functions in the VTA-NAc pathway. CREB function is a major theme of this Center. All of the subsequent Projects of this Grant represent extensions of our central hypothesis that CREB in the VTA-NAc is a key regulator of hedonic and affective state. Subsequent Projects extend this theme by examining other molecular constituents of VTA and NAc neurons, which are regulated by CREB (e.g., BDNF in Project 2, CCK in Project 4) and help control CREB activity (e.g., MCH in Project 3), and by characterizing their role in mediating CREB's complex behavioral phenotype related to depression and its treatment.

项目1重点关注NAc（伏隔核）中转录因子CREB的调节能力 情绪和动机状态。我们有相当多的证据表明在这个大脑中CREB功能的增加 在几种主动应激条件下出现的区域，导致动物敏感性下降 情绪刺激，不管刺激是令人厌恶的还是有益的。相反，CREB降低 功能，由于缺乏情感刺激（例如，长期的社会隔离，有相反的效果。 这些发现表明，NAc中的CREB可能是情绪和情感之间的关键分子门。 刺激及其行为反应。CREB活性的两个极端之间可能存在关系， 在人类抑郁症的各种亚型中看到的不同范围的症状将在 动物模型例如，初步数据显示，NAc中CREB活性的极端变化 （过高或过低的活动）及其行为后果，可以通过以下方式加以纠正： 慢性而非急性的抗抑郁治疗相关的研究将描述靶基因， CREB在NAc中产生这种行为表型。编码阿片肽强啡肽和 AMPA谷氨酸受体亚单位GluR 1是CREB靶点的实例，将在 这个项目，将与DNA表达阵列和芯片上的ChIP（染色质）确定的其他目标一样， 免疫沉淀X启动子）阵列。ChIP还将用于表征分子机制， 其中CREB在染色质重塑水平上调节其靶基因。此外，该项目将 研究CREB在腹侧被盖区（VTA）调节抑郁样 行为，以及建立其他几个CREB家族蛋白的行为表型，我们 最近已经显示在VTA-NAc通路中具有非常不同的功能。 CREB功能是该中心的一个主要主题。本补助金的所有后续项目均代表 扩展了我们的中心假设，即VTA-NAc中的CREB是享乐和情感的关键调节因子， 状态随后的项目通过研究VTA和NAc的其他分子成分来扩展这一主题 神经元，受CREB调节（例如，BDNF在项目2中，CCK在项目4中）并帮助控制CREB 活动（例如，项目3中的MCH），并通过表征它们在介导CREB复杂行为中的作用， 与抑郁症相关的表型及其治疗。