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NAc（伏隔核）中的转录因子CREB调节的能力 情绪和动机状态。我们有大量证据表明大脑中的 CREB ​​功能增强 在几种主动应激条件下发生的区域会导致动物敏感性下降 情绪刺激，无论刺激是令人厌恶的还是有益的。相反，减少 CREB 由于缺乏情绪刺激（例如，长期的社会孤立）而导致的功能障碍，会产生相反的效果。 这些发现表明，NAc 中的 CREB ​​可能作为情绪之间的关键分子门发挥作用。 刺激及其行为反应。 CREB ​​活动的两个极端之间可能存在关系 人类抑郁症不同亚型中出现的不同症状范围将在以下方面进一步探讨 动物模型。例如，初步数据表明，NAc 中 CREB ​​活性的极端变化 （活动过高或过低）及其行为后果可以通过以下方式纠正： 慢性而非急性抗抑郁治疗。相关研究将通过表征靶基因 CREB ​​在 NAc 中产生这种行为表型。编码阿片肽强啡肽的基因和 AMPA 谷氨酸受体亚基 GluR1 是 CREB ​​此类靶标的例子，将在 该项目以及通过 DNA 表达阵列和芯片上 ChIP 识别的其他目标（染色质 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，该项目还将 研究 CREB ​​在 VTA（腹侧被盖区）调节抑郁样症状中的作用 行为，以及建立其他几个 CREB ​​家族蛋白的行为表型，我们 最近的研究表明，VTA-NAc 通路具有非常不同的功能。 CREB功能是该中心的一大主题。本次资助的所有后续项目代表 我们中心假设的延伸，即 VTA-NAc 中的 CREB ​​是享乐和情感的关键调节器 状态。后续项目通过检查 VTA 和 NAc 的其他分子成分来扩展这一主题 神经元，受 CREB ​​调节（例如项目 2 中的 BDNF，项目 4 中的 CCK）并帮助控制 CREB 活动（例如项目 3 中的 MCH），并通过描述其在调解 CREB ​​复杂行为中的作用 与抑郁症及其治疗相关的表型。