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: 7905907
• 负责人: RONALD S. DUMAN
• 金额: $ 29.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7905907
• 关键词: Acute; Affective; Animal Model; Animals; Antidepressive Agents; Appetitive Behavior; Behavior; Behavioral; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Candidate Disease Gene; Cholecystokinin; Chronic; Complex; DNA; Data; Dynorphins; Emotional; Gene Targeting; Genes; Glutamate Receptor; Grant; Human; Knockout Mice; Mediating; Molecular; Moods; Motivation; Neurons; Nucleus Accumbens; Opioid Peptide; Pathway interactions; Phenotype; Play; Protein Family; Regulation; Rewards; Role; Social isolation; Stimulus; Stress; Symptoms; Ventral Tegmental Area; chromatin immunoprecipitation; chromatin remodeling; depression; emotional stimulus; hedonic; mood regulation; promoter; relating to nervous system; 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侧重于研究伏隔核中转录因子CREB的调控能力