NGF AND CHOLINERGIC FUNCTION IN ADULT AND AGING BRAIN

这项研究的主要目标是描述 外源性神经生长因子对胆碱能神经的作用 投射系统内的神经传递和突触功能 正常成人和老年人的基底前脑胆碱能神经元 哺乳动物的大脑。正在寻求这种理解，以确定 事实证明，使用NGF治疗在维持和/或恢复方面可能有效 大鼠前脑胆碱能投射的功能完整性 患有与年龄相关的神经退行性疾病的人， 尤其是阿尔茨海默病(AD)。这项工作是以先前为前提的。 了解神经生长因子刺激多种胆碱能物质的表达 啮齿动物前脑区的神经元特征--一个主要目标是 确定此类影响可能对 BFCN与其突触后靶细胞之间的神经传递。至 为此，电流钳位和单电极电压钳位 将使用技术在细胞内记录胆碱能效应 刺激基底核的前脑传入所产生的 杏仁基底外侧核的大细胞至甲状核神经元 大鼠脑片制备。前脑胆碱能神经生长因子相关变化的研究 神经传递将通过比较NBM的能力来评估 诱发胆碱能慢除极的刺激及其基础 突触电流和抑制几种内源性膜钾 对照组和NGF处理组大鼠脑片中BLA神经元的电导。 对照和NGF处理的神经元对沐浴应用的反应 胆碱能激动剂将进行比较，以解决以下可能性 神经营养因子治疗可能导致突触后改变 胆碱能敏感性。此外，我们还将测量 胆碱乙酰转移酶(ChAT)与组织高亲和力胆碱摄取 从许多相同的准备中提取的样本，在这些准备中，录音将 以确定NBM介导的任何NGF相关变化 BLA内的突触活动可能与突触前的改变有关 调节乙酰胆碱(ACh)合成和/或释放的机制。 此外，还将对以下物质引起的~3H-ACh释放进行比较 电场刺激对对照组杏仁核脑片的影响 和NGF处理的大鼠直接确定NGF治疗是否 导致发射器从NBM的终端上方便地释放 胆碱能神经元。这些研究将在大脑中进行 取自幼年成年动物的切片和从 老龄大鼠处于不同衰老阶段。整体而言，建议的 研究的目的是提供一个全面的图景能力 外源性NGF在条件下维持中枢胆碱能传递 与衰老过程相关的胆碱能神经退行性变 与患者的神经病理特征相似 广告。

The primary goal of this research is to characterize the effects of administration of exogenous nerve growth factor (NGF) on cholinergic neurotransmission and synaptic function within the projection systems of basal forebrain cholinergic neurons (BFCN) in both normal adult and aged mammalian brain. This understanding is being sought to determine whether treatment with NGF might prove effective in maintaining and/or restoring the functional integrity of forebrain cholinergic projections in individuals suffering from age-related neurodegenerative disorders, particularly Alzheimer's disease (AD). The work is predicated on prior knowledge that NGF stimulates the expression of a host of cholinergic neuronal traits in forebrain areas in rodents -- a major objective is to determine the functional significance that such effects might have on neurotransmission between BFCN and their postsynaptic target cells. To accomplish this, current-clamp and single electrode voltage-clamp techniques will be used to intracellularly record cholinergic effects produced by stimulation of forebrain inputs from nucleus basalis magnocellularis (NBM) to pyrmaidal neurons in basolateral amygdala (BLA) in rat brain slice preparations. NGF-related changes in forebrain cholinergic neurotransmission will be assessed by comparing the ability of NBM stimulation to elicit a cholinergic slow depolarization and its underlying synaptic current and to inhibit several intrinsic membrane potassium conductances in BLA neurons in slices from control and NGF-treated rats. The responses of control and NGF-treated neurons to bath application of cholinergic agonists will be compared to address the possibility that treatment with the neurotrophic factor might induce changes in postsynaptic cholinergic sensitivity. In addition, we will measure the activity of choline acetyltransferase (ChAT) and high affinity choline uptake in tissue samples taken from many of the same preparations in which recordings will be obtained to determine whether any NGF-related changes in NBM-mediated synaptic action within the BLA can be linked to alterations in presynaptic mechanisms that regulate acetylcholine (ACh) synthesis and/or release. Additional comparisons will be made of the release of 3H-ACh evoked by electrical field stimulation in slices of amygdala prepared from control and NGF-treated rats to directly ascertain whether treatment with NGF results in a facilitated release of transmitter from terminals of NBM cholinergic neurons. These investigations will be carried out in brain slices taken from young adult animals and in preparations obtained from aged rats at different stages of senescence. Overall, the proposed research is designed to provide a comprehensive picture of the ability of exogenous NGF to maintain central cholinergic transmission under conditions of cholinergic neurodegeneration that are associated with the aging process and which approximate the neuropathological profile found in patients with AD.