Neural Substrates /Appetitive Behavior /Mood /Motivation

描述(申请人提供)：这个新的孔特中心的目标是研究大脑的食欲神经回路在情绪和动机调节中的作用，因为它们与抑郁和抗抑郁行为有关。这项研究计划包含三个主要优势。首先，是我们正在进行的和拟议的研究的多学科性质。每个研究领域代表了分子、细胞、药理学和行为水平的综合分析，旨在更全面地了解情绪的神经生物学。第二，是我们的基础科学研究与临床人群调查的结合。第三，是各种项目的超常整合程度，以检验中心中心高度相关的方面的假设。虽然对抑郁症的研究主要集中在海马体和大脑皮层，但其他可能涉及的神经回路得到的关注要少得多。该中心专注于这些其他环路中的一个，即大脑的食欲区域，包括伏隔核和下丘脑，对动机、奖励、食欲、睡眠、精神运动活动和昼夜节律至关重要。考虑到抑郁症和其他情绪障碍患者在这些不同领域的异常程度，对这些食欲回路的关注是有意义的。事实上，在这项应用中，我们已经获得了大量的证据，证明了这些食欲回路在抑郁症动物模型中的重要性。该中心由一个小型协调核心、两个科学核心和五个项目组成。转基因核心负责向中心研究人员提供最先进的分子工具，而行为核心负责向个别项目提供与情绪和动机相关的极其广泛的小鼠和大鼠行为测试。项目1的重点是转录因子CREB，它是食欲回路的关键调节因子，以及它在情绪和动机中的作用。随后的项目评估了这些神经通路中的一系列其他分子信号，这些信号既是CREB功能的重要调节因素，也是调节CREB行为表型的重要效应者。项目2侧重于脑源性神经营养因子；项目3侧重于下丘脑多肽，即MSH、增食欲素和MCH；项目4侧重于NPAS2和其他昼夜节律基因；项目5侧重于RGS蛋白，特别是RGS9和RGS16。

DESCRIPTION (provided by applicant): The objective of this new Conte Center is to study the role of the brain's appetitive neural circuits in the regulation of mood and motivation as they relate to depression and antidepressant action. The program of research contains three major strengths. First, is the multidisciplinary nature of our ongoing and proposed research. Each research area represents an integration of molecular, cellular, pharmacological, and behavioral levels of analysis aimed at obtaining a more complete understanding of the neurobiology of mood. Second, is the integration of our basic science research with the investigation of clinical populations. Third, is the extraordinary degree of integration of the various Projects to examine highly related aspects of the central hypothesis of the Center. While research in depression has focused largely on hippocampus and cerebral cortex, other neural circuits possibly involved have received much less attention. This Center focuses on one of these other circuits, namely, appetitive regions of brain, including nucleus accumbens and hypothalamus, important for motivation, reward, appetite, sleep, psychomotor activity, and circadian rhythms. A focus on these appetitive circuits makes sense given the degree to which abnormalities in these various domains are seen in patients with depression and other mood disorders. Indeed, we have obtained substantial evidence, presented in this application, for the importance of these appetitive circuits in animal models of depression. The Center is organized into a small Coordination Core, two scientific Cores, and five Projects. The Transgenic Core is responsible for providing state-of-the-art molecular tools to Center investigators, while the Behavioral Core is responsible for providing to individual Projects an extremely broad battery of behavioral tests in mice and rats relevant to mood and motivation. Project 1 is focused on the transcription factor CREB as a key regulator of appetitive circuits and its role in mood and motivation. Subsequent Projects evaluate a series of other molecular signals in these neural pathways that are both important regulators of CREB function and important effectors in mediating CREB's behavioral phenotype. Project 2 focuses on BDNF; Project 3 focuses on three hypothalamic peptides, MSH, orexin (hypocretin), and MCH; Project 4 focuses on NPAS2 and other circadian genes; Project 5 focuses on RGS proteins, in particular, RGS9 and RGS16.