Neural Substrates of Appetitive Behavior in Mood and Motivation

描述(申请者提供)：项目1重点研究伏隔核中转录因子CREB调节情绪和动机状态的能力。我们有相当多的证据表明，在几种积极应激条件下，大脑这一区域CREB功能的增加会导致动物对情绪刺激的敏感度降低，无论刺激是厌恶的还是有益的。相反，由于缺乏情感刺激(例如，长期的社会隔离)而导致的CREB功能下降具有相反的效果。这些发现表明，NAC中的CREB可能是情绪刺激及其行为反应之间的关键分子门。CREB活性的两个极端与人类抑郁症不同亚型中出现的不同症状范围之间的可能关系将在动物模型中进一步探索。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，都可以通过慢性而不是急性的抗抑郁药物治疗来纠正。相关研究将确定CREB在NAC中产生这种行为表型的靶基因。编码阿片肽强啡肽和AMPA谷氨酸受体亚单位GluR1的基因是CREB的这种靶点的例子，将在本项目中进行研究，以及通过DNA表达阵列和芯片(染色质免疫沉淀x启动子)阵列确定的其他靶点。芯片还将被用来描述CREB在染色质重塑水平上调节其目标基因的分子机制。此外，该项目还将研究CREB在腹侧被盖区(VTA)中的作用，以及建立其他几个CREB家族蛋白的行为表型，我们最近发现这些蛋白在VTA-NAC途径中具有非常不同的功能。CREB功能是该中心的一大主题。这项研究的所有后续项目都代表了我们的核心假设的扩展，即VTA-NAC中的CREB是享乐性和情感状态的关键调节因子。随后的项目通过研究受CREB调控的VTA和NAC神经元的其他分子成分(例如，项目2中的BDNF，项目4中的CCK)并帮助控制CREB的活动(例如，项目3中的MCH)，以及通过表征它们在调节CREB与抑郁症及其治疗相关的复杂行为表型中的作用，扩展了这一主题。

DESCRIPTION (provided by applicant): 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.