EXOGENOUS CHOLINE: EFFECTS ON ACH FUNCTION IN BRAIN

这项研究的主要目的是阐明机制 调节神经递质乙酰胆碱（ACh）的合成， 大脑，重点是确定如何改变可用性 胆碱前体的改变这些过程。有证据表明， 一种假设，即大脑中胆碱的供应增加， 乙酰胆碱合成的底物，只有当 神经递质的合成是刺激的结果， 增加ACh释放。虽然这种效果在急性 胃肠外给予胆碱，尚未证明 尽管有证据表明， 治疗增加脑中胆碱的可用性。此外，当 火胆碱被排除在饮食之外，尽管稳态水平的 胆碱在大脑中是不变的，游离氯的动员， 酯化的来源减少，伴随着合成的减少， 的ACh。因此，本提案的具体目的是阐明 调节脑中ACh合成的神经化学机制， 在亚细胞水平上，确定胆碱 可用性调节这些过程。概述的研究将使用 结合体内/体外方法，并研究急性 氯的管理，以及慢性饮食的后果， 改变;对于后者，大鼠将维持在缺乏氯的环境中。 或补充氯的饮食一个月。这些脑切片 动物将用于体外神经化学研究。的 乙酰胆碱的合成和释放，游离氯的释放和产生， 以及提供乙酰胆碱前体的氯的酯化来源 合成将以来自脑区域的亚细胞级分为特征 其含有大量的胆碱能神经末梢，即， 纹状体海马和大脑皮层具体来说，实验 将调查：1）负责的亚细胞机制， 增加合成乙酰胆碱在脑片从氯注射大鼠时， 这些切片暴露于刺激物， 通过增加神经递质释放; 2）是否慢性（饮食） 补充氯对胆碱能神经元有直接作用， 观察到的体内效应是否继发于全身性膜 磷脂扰动; 3）介导降低的机制 从喂食胆碱缺乏饮食的大鼠脑中合成ACh;和4） 神经元活动之间的相互作用，胆碱的需求， 磷脂和乙酰胆碱代谢。这些研究的结果将决定 酯化胆碱池的性质和定位， 乙酰胆碱合成的游离胆碱，以及这种来源是如何通过 改变了前体的可用性。这些知识对于一个 对大脑功能以及这种功能如何受损的基本了解 通过饮食限制必需营养素如胆碱。 此外，研究结果将为制定可能的 治疗神经精神障碍的治疗策略 假设涉及中枢胆碱能活动减退，如阿尔茨海默氏症 疾病

The major goal of this research proposal is to elucidate the mechanisms regulating the synthesis of the neurotransmitter acetylcholine (ACh) in brain, with an emphasis on determining how alterations in the availability of the precursor choline modify these processes. Evidence has supported the hypothesis that an increased supply of choline to the brain provides substrate for ACh synthesis that is of functional significance only when neurotransmitter synthesis is increased as a consequence of stimuli that increase ACh release. While this effect is manifest following the acute parenteral administration of choline, it has not been demonstrated following chronic dietary supplementation, despite evidence that both treatments increase choline availability in the brain. Furthermore, when fire choline is excluded from the diet, although steady-state levels of choline in brain are unaltered, the mobilization of free chorine from esterified sources decreases, with a concomitant reduction in the synthesis of ACh. Thus, the specific aim of this proposal is to elucidate the neurochemical mechanisms regulating the synthesis of ACh in brain, and determine, at the subcellular level, how alterations in choline availability modulate these processes. The studies outlined will use a combined in vivo/in vitro approach and investigate the effects of acute chorine administration, as well as the consequences of chronic dietary alterations; for the latter, rats will be maintained on chorine-deficient or chorine-supplemented diets for one month. Brain slices from these animals will be used for neurochemical investigations in vitro. The synthesis and release of ACh, the release and production of free chorine, and the esterified sources of chorine that provide precursor for ACh synthesis will be characterized in subcellular fractions from brain regions that contain a dense population of cholinergic nerve terminals, viz., striatum, hippocampus, and cerebral cortex. Specifically, the experiments will investigate: 1) the subcellular mechanisms responsible for the increased synthesis of ACh in brain slices from chorine-injected rats when these slices are exposed to stimuli that increase the demand for precursor by increasing neurotransmitter release; 2) whether chronic (dietary) supplementation with chorine has a direct effect on cholinergic neurons or whether observed in vivo effects are secondary to generalized membrane phospholipid perturbations; 3) the mechanism mediating the decreased synthesis of ACh in brain from rats fed a choline-deficient diet; and 4) the interactions among neuronal activity, the demand for choline, and phospholipid and ACh metabolism. Results from these studies will determine the nature and localization of the esterified choline pool that supplies free choline for ACh synthesis, and how this source is modulated by altering the availability of precursor. This knowledge is essential for a basic understanding of brain function and how such function can be impaired by the dietary restriction of an essential nutrient such as choline. Furthermore, results will provide a basis for the development of possible therapeutic strategies for the treatment of neuropsychiatric disorders postulated to involve central hypocholinergic activity such as Alzheimer's disease.