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: 7664379
• 负责人: RONALD S. DUMAN
• 金额: $ 31.42万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664379
• 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重点研究伏隔核中转录因子CREB的调节能力。 情绪和动机状态。我们有相当多的证据表明大脑中CREB功能增强 在几种活动应激条件下出现的区域，会导致动物的敏感度降低 对情绪的刺激，无论刺激是令人厌恶的还是有益的。相反，减少CREB 缺乏情感刺激(例如，长期的社会孤立)所造成的功能障碍，会产生相反的效果。 这些发现表明，NAC中的CREB可能是情绪之间的关键分子门 刺激及其行为反应。CREB活性和CREB活性两个极端之间的可能关系 在人类抑郁的不同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活动的极端变化 (活跃度过高或过低)及其行为后果可以通过以下方式纠正 慢性的、非急性的抗抑郁治疗。相关研究将鉴定靶基因，通过这些基因 CREB在NAC产生这种行为表型。编码阿片肽强啡肽的基因和 AMPA谷氨酸受体亚单位GluR1是CREB的这种靶点的例子，将在 这个项目，以及通过DNA表达阵列和芯片(染色质)确定的其他目标 免疫沉淀x启动子)阵列。芯片也将被用来表征分子机制，通过 其中CREB在染色质重塑水平上调节其靶基因。此外，该项目将 探讨腹侧被盖区CREB在调节抑郁样病变中的作用 行为，以及建立其他几个CREB家族蛋白的行为表型，我们 最近发现在VTA-NAC通路中具有非常不同的功能。 CREB功能是该中心的一大主题。该赠款的所有后续项目均代表 我们中心假设的扩展，即VTA-NAC中的CREB是享乐性和情感性的关键调节因子 州政府。后续项目通过研究VTA和NAC的其他分子成分来扩展这一主题 受CREB调控的神经元(例如，项目2中的BDNF，项目4中的CCK)，帮助控制CREB 活动(例如，项目3中的妇幼保健)，并通过表征它们在调节CREB复杂行为中的作用 与抑郁症相关的表型及其治疗。