COBRE: UMMC: GALANIN IN LOCUS COERULEUS - VENTRAL TEGMENTAL AREA AXONS

COBRE：UMMC：蓝斑中的甘丙肽 - 腹侧被盖区轴突

• 批准号: 7381917
• 负责人: KIMBERLY L SIMPSON
• 金额: $ 13.27万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381917
• 关键词: COBRE; UMMC; GALANIN; LOCUS; COERULEUS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The noradrenergic locus coeruleus (LC) and serotonergic dorsal raphe (DR) nucleus are two brainstem centers that have been implicated in major depressive disorder. These systems are widely projecting and have the potential to globally impact brain function. Despite the broad distribution of norepinephrine (NE)- and serotonin (5HT)-containing axons within the CNS, a number of studies indicate that subpopulations of LC and DR neurons can be discriminated on the basis of neurochemical content and target specificity. This suggests that under certain behavioral or physiological conditions, subgroups of LC and DR neurons may selectively influence the activity of particular neuronal circuits. The lab has pursued this concept by examining the innervation of structures associated with the ascending trigeminal somatosensory system by LC and DR. In these investigations it was revealed that the major output from one LC nucleus is organized with respect to the crossed trajectory of this modality specific pathway, and that there is a propensity for individual LC neurons to send axon collaterals to neuronal ensembles engaged in similar sensory functions. Other recent findings indicate that cortical nitric oxide synthase (NOS)-containing axons originate from discrete clusters of DR neurons located primarily along the ventral midline. State-of-the-art tract tracing, immunohistochemical, and electron microscopic techniques are also being utilized in current studies which are aimed at exploring the role of the neuropeptide, galanin (Gal), in depression. A major focus of this work is to explore an existing hypothesis which states that LC-derived Gal may negatively impact dopamine output from the ventral tegmental area (VTA) and contribute to symptomatology observed in depression, i.e. decreased motor activity and decreased appreciation of pleasurable stimuli. More specifically, the lab is interested in defining the chemoarchitecture of the LC-VTA projection, and characterizing the synaptic organization of LC-VTA axon terminals relative to mesolimbic and mesocortical projection neurons. On-going work is also directed toward examining the effect of enhanced levels of LC activity on Gal and dopamine-beta-hydroxylase (DBH) expression. Since animal models of depression manifest increased levels of LC activity and suicide victims demonstrate elevated levels of LC tyrosine hydroxylase, it stands to reason that depression-related increases in LC activity may alter the synthesis and availability of Gal and NE in LC terminals. This issue and the possibility that dysregulation of LC firing may modify the synaptic relationship between LC and VTA, are being examined in studies where levels of LC activation are manipulated and correlated with changes in Gal- and DBH-positive VTA fiber density, morphology, and ultrastructure.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。去甲肾上腺素能蓝斑核（LC）和血清素能中背核（DR）是两个与重度抑郁症有关的脑干中枢。这些系统具有广泛的投射性，有可能在全球范围内影响大脑功能。尽管在中枢神经系统中含有去甲肾上腺素（NE）和5 -羟色胺（5HT）的轴突分布广泛，但许多研究表明，LC和DR神经元的亚群可以根据神经化学成分和靶特异性进行区分。这表明在某些行为或生理条件下，LC和DR神经元亚群可能选择性地影响特定神经元回路的活动。该实验室通过LC和dr检查与上升三叉躯体感觉系统相关的结构的神经支配来追求这一概念。在这些研究中发现，一个LC核的主要输出是按照这一模态特定途径的交叉轨迹组织的，并且单个LC神经元有向参与类似感觉功能的神经元群发送轴突侧枝的倾向。最近的其他研究结果表明，皮质一氧化氮合酶（NOS）的轴突起源于主要沿腹中线分布的DR神经元的离散簇。目前的研究也利用了最先进的神经束示踪、免疫组织化学和电子显微镜技术，旨在探索神经肽甘丙氨酸（Gal）在抑郁症中的作用。本研究的一个主要重点是探索一个现有的假设，该假设认为lc衍生的Gal可能会对腹侧被盖区（VTA）的多巴胺输出产生负面影响，并有助于观察到抑郁症的症状，即运动活动减少和对愉悦刺激的欣赏减少。更具体地说，该实验室感兴趣的是定义LC-VTA投射的化学结构，并表征LC-VTA轴突末端相对于中边缘和中皮层投射神经元的突触组织。正在进行的研究还旨在研究LC活性水平提高对Gal和多巴胺- β -羟化酶（DBH）表达的影响。由于抑郁症动物模型显示LC活性水平升高，自杀受害者显示LC酪氨酸羟化酶水平升高，因此抑郁症相关的LC活性增加可能会改变LC末端Gal和NE的合成和可用性。这个问题和LC放电失调可能改变LC和VTA之间突触关系的可能性，正在研究中进行检验，其中LC激活水平被操纵，并与Gal-和dbh阳性VTA纤维密度、形态和超微结构的变化相关。