EXOGENOUS CHOLINE: EFFECTS ON ACH FUNCTION IN BRAIN

这项研究计划的主要目的是阐明其作用机制。 神经递质乙酰胆碱(ACh)的合成 Brain，重点是确定可用性中的变化 前体胆碱可以改变这些过程。有证据表明， 一种假说，即增加脑部胆碱供应可提供 仅在以下情况下才具有功能意义的ACh合成底物 神经递质合成作为刺激的结果是增加的 增加ACh的释放。而这种影响在急性发作后明显 肠外注射胆碱，这还没有得到证实 在长期饮食补充后，尽管有证据表明 治疗增加了大脑中胆碱的可获得性。此外，当 火胆碱被排除在饮食之外，尽管稳定的水平 大脑中的胆碱是不变的，从 酯化来源减少，合成过程中随之减少。 当然了。因此，这项提案的具体目的是澄清 调节大脑中ACh合成的神经化学机制，以及 在亚细胞水平上确定胆碱的变化 可用性调节了这些过程。概述的研究将使用 体内/体外相结合的方法，并考察急性 氯化吸入，以及慢性饮食的后果 改变；对于后者，大鼠将维持在氯素缺乏上 或补充氯仿的饮食，为期一个月。从这些脑片中取出 动物将被用于体外神经化学研究。这个 乙酰胆碱的合成和释放，游离氯的释放和生产， 以及为ACh提供前体的氯化的酯化来源 合成将以来自大脑区域的亚细胞部分为特征 它们含有密集的胆碱能神经末梢，即 纹状体、海马体和大脑皮层。具体来说，这些实验 将调查：1)亚细胞机制负责 氯化可致大鼠脑片ACh合成增加 这些切片暴露在刺激下，增加了对前体的需求 通过增加神经递质的释放；2)是否慢性(饮食) 补充氯化可直接影响胆碱能神经元或 体内观察到的效应是否继发于全身膜 磷脂微扰；3)调节降低的机制 胆碱缺乏饮食大鼠脑内乙酰胆碱的合成； 神经元活动、对胆碱的需求和 磷脂和ACh代谢。这些研究的结果将决定 供应的酯化胆碱池的性质和定位 ACh合成的游离胆碱，以及这一来源是如何被 改变前体的可获得性。这方面的知识对于 对大脑功能的基本了解以及这种功能是如何受损的 通过限制饮食中的基本营养素，如胆碱。 此外，结果将为可能的开发提供基础 神经精神障碍的治疗策略 推测涉及中枢性低胆碱能活动，如阿尔茨海默病 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.