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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 去甲肾上腺素能蓝斑（LC）和肾上腺素能中缝背核（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射性，并有可能在全球范围内影响大脑功能。尽管广泛分布的去甲肾上腺素（NE）和5-羟色胺（5-HT）的轴突在中枢神经系统内，一些研究表明，LC和DR神经元的亚群可以区分的基础上的神经化学成分和目标的特异性。这表明，在某些行为或生理条件下，LC和DR神经元的亚组可能会选择性地影响特定神经元回路的活动。该实验室通过检查与LC和DR的三叉神经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，发现来自一个LC核的主要输出是相对于该模态特定通路的交叉轨迹组织的，并且存在单个LC神经元将轴突侧支发送到参与类似感觉功能的神经元集合的倾向。其他最近的研究结果表明，皮质一氧化氮合酶（NOS）的轴突起源于离散的DR神经元主要位于沿着腹侧中线的集群。 国家的最先进的跟踪，免疫组织化学和电子显微镜技术也被用于目前的研究，旨在探索神经肽，甘丙肽（Gal），在抑郁症中的作用。这项工作的一个主要重点是探索现有的假设，该假设指出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，并有助于在抑郁症中观察到的抑郁症，即运动活动减少和对愉快刺激的欣赏减少。更具体地说，该实验室有兴趣定义LC-VTA投射的化学结构，并表征LC-VTA轴突终末相对于中边缘和中皮层投射神经元的突触组织。正在进行的工作也针对检查增强水平的LC活性对Gal和多巴胺-β-羟化酶（DBH）表达的影响。由于抑郁症的动物模型表现出增加水平的LC活性和自杀的受害者表现出升高水平的LC酪氨酸羟化酶，它站在理由，抑郁症相关的LC活性的增加可能会改变合成和可用性的半乳糖和NE在LC终端。这个问题和可能性，LC放电失调可能会修改LC和腹侧被盖区之间的突触关系，正在研究中LC激活水平的操纵和相关的变化半乳糖和DBH阳性腹侧被盖区纤维密度，形态和超微结构。

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.