PRESYNAPTIC NEUROCHEMICAL MARKERS

这个项目中提出的实验将阐明 配体结合位点标记之间的重要关系 胆碱能或多巴胺能神经元及其完整性 以及它们在大脑中终末的密度。我们将寻求 要区分那些动态响应的标记 突触活动的扰动来自其标志物 表达似乎只与完好无损的生存有关 突触前神经末梢。前者可能在以下方面有用 阐明对疾病的调控反应或遵循 治疗，但不能作为可靠的定量 神经元密度的标记物。满足后者的标记 标准非常适合于前瞻性分析。 神经退行性变的疾病和治疗干预 疾病，潜在地提供客观的衡量标准 进展或反应。确定这种情况的能力 非侵入性临床环境中的标记物，使用 发射断层成像，最终可能允许 神经元存活和死亡笔记的详细分析 以前是有可能的。 我们的假设集中在放射性配体的研究上。 突触膜上的结合部位 胆碱能或单胺能特异的囊泡 神经元。配体[~3H]维沙米考和 [~3H]甲氧基四苯肼将应用于评价 分别在这些神经元群体中。我们会 比较神经生物学的表达和调控 这些结合位点带有额外的细胞措施 突触前摄取的膜转运部位 胆碱或多巴胺。监管方面的变化 这两个地点的活动在本案中是众所周知的 胆碱能神经元，并可能存在于 还有多巴胺能神经末梢。我们的实验 设计将涉及慢性给药的使用 在动物身上产生突触活动的改变，通过 增强或抑制神经传递的。在这些下面 神经递质的状态、调节调节 数字是已知的，允许平行出现 记录突触活动的改变状态。 然后我们将确定可能出现的更改 突触小泡和突触前膜摄取部位。 以上药物挑战和药物挑战结果的比较 那些跟踪选择性脑损伤的研究，导致 皮质胆碱能缺陷或纹状体多巴胺能 缺陷，将用配体结合标记在 阿尔茨海默病患者的尸检脑组织样本 和帕金森氏症。综合起来，这些结果将 增进对以下方面的相关贡献的理解 神经元丢失和二次调节反应 这些特发性疾病。未来的临床研究 基于精心挑选的突触标志物的研究 诚信，那么就有可能了。

The experiments proposed in this project will elucidate important relationships between ligand binding site markers of cholinergic or dopaminergic neurons and the integrity and density of their terminals in the brain. We will seek to distinguish those markers that respond dynamically to perturbations in synaptic activity from markers whose expression appears related only to the survival of intact presynaptic nerve endings. The former may be of utility in elucidating regulatory responses to disease or following treatment, but will not serve as reliable quantitative markers of neuronal density. Markers satisfying the latter criterion are well-suited to the prospective analysis of disease and therapeutic interventions in neurodegenerative disorders, potentially providing objective measures of progression or response. The capability to determine such markers in noninvasive clinical settings, with the use of emission tomographic imaging, may ultimately permit detailed analyses of neuronal survival and death not previously possible. Our hypotheses are focused on the study of radioligand binding sites located on the membranes of synaptic vesicles, specific to cholinergic or to monoaminergic neurons. The ligands [3H]vesamicol and [3H]methoxytetrabenazine will be applied to the evaluation of these neuronal populations, respectively. We will compare the neurobiologic expression and regulation of these binding sites with additional measures of cell membrane transport sites for the presynaptic uptake of choline or of dopamine. Regulatory changes in the activities of these latter sites are well-known in the case of cholinergic neurons, and are potentially present in dopaminergic nerve terminals as well. Our experimental design will involve the use of chronic drug administration in animals to produce alterations in synaptic activity by potentiating or inhibiting neurotransmission. Under these conditions, regulatory modulation in neurotransmitter numbers are known to occur, permitting parallel documentation of the altered state of synaptic activity. We will then determine the possible presence of changes in the synaptic vesicle and presynaptic membrane uptake sites. Comparison of the above results of drug challenges and those following selective brain lesions, resulting in cortical cholinergic deficits or in striatal dopaminergic deficits, will be make with ligand binding markers in postmortem brain samples from subjects with Alzheimers's and Parkinson's diseases. Combined, these results will enhance understanding of the relateive contributions of neuronal loss and of secondary regulatory responses in these idiopathic disorders. Future clinical research studies, based on carefully-chosen markers of synaptic integrity, will then be possible.