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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。去甲肾上腺素能蓝斑(LC)和5-羟色胺能中缝背核(DR)是两个与抑郁症有关的脑干中枢。这些系统具有广泛的投影性，有可能影响全球的大脑功能。尽管含去甲肾上腺素(NE)和5-羟色胺(5-HT)的轴突在中枢神经系统中广泛分布，但许多研究表明，可以根据神经化学成分和靶标的特异性来区分LC和DR神经元的亚群。这表明在特定的行为或生理条件下，LC和DR神经元的亚群可能选择性地影响特定神经元回路的活动。实验室通过研究LC和DR对与三叉神经体感系统上升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核的主要输出是相对于这一特定通道的交叉轨迹组织的，并且单个LC神经元有将轴突侧支发送到参与类似感觉功能的神经元群的倾向。最近的其他发现表明，皮质一氧化氮合酶(NOS)轴突起源于主要位于腹中线的离散的DR神经元簇。目前旨在探索神经肽甘丙素(Galanin，Gal)在抑郁症中的作用的研究也利用了最先进的轨迹追踪、免疫组织化学和电子显微镜技术。这项工作的一个主要焦点是探索一个现有的假设，即LC来源的Gal可能对腹侧被盖区(VTA)的多巴胺输出产生负面影响，并有助于在抑郁症中观察到的症状，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轴突终末相对于中脑边缘和中皮质投射神经元的突触组织。正在进行的工作也针对检查增强水平的LC活性对半乳糖和多巴胺-β-羟基酶(DBH)表达的影响。由于抑郁症动物模型表现为LC活性升高，而自杀者表现为LC酪氨酸羟基酶水平升高，因此与抑郁症相关的LC活性增加可能改变LC终末Gal和NE的合成和可获得性。这一问题以及LC放电异常可能改变LC和VTA之间的突触关系的可能性正在研究中，其中LC的激活水平受到控制，并与Gal和DBH阳性VTA纤维密度、形态和超微结构的变化相关。

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.