NGF AND CHOLINERGIC FUNCTION IN ADULT AND AGING BRAIN

本研究的主要目的是描述 外源性神经生长因子（NGF）对胆碱能神经元的作用 投射系统内的神经传递和突触功能 正常成人和老年人基底前脑胆碱能神经元 哺乳动物的大脑 目前正在寻求这一谅解，以确定 用神经生长因子治疗可以有效地维持和/或恢复 前脑胆碱能投射的功能完整性 患有与年龄相关的神经变性疾病的个体， 特别是阿尔茨海默病（AD）。 这项工作是以先前的 神经生长因子刺激胆碱能受体表达的知识， 啮齿动物前脑区域的神经元特征--一个主要目的是 确定这些影响可能对 BFCN和它们的突触后靶细胞之间的神经传递。 到 实现这一点，电流钳和单电极电压钳 技术将用于细胞内记录胆碱能效应 由基底核的前脑输入刺激产生 大细胞（NBM）的基底外侧杏仁核（BLA）的pyrmaidal神经元 大鼠脑切片制备。 神经生长因子相关的前脑胆碱能变化 神经传递将通过比较NBM的能力来评估 刺激引起胆碱能缓慢去极化及其潜在的 突触电流和抑制几种内在膜钾 在来自对照和NGF处理的大鼠的切片中BLA神经元的电导。 对照和NGF处理的神经元对浴应用的反应 将比较胆碱能激动剂，以解决以下可能性： 用神经营养因子治疗可能会引起突触后神经元的变化。 胆碱能敏感性 此外，我们还将测量 胆碱乙酰转移酶（ChAT）和组织中的高亲和力胆碱摄取 从许多相同的制备中提取的样品，其中记录将 以确定是否有任何神经生长因子相关的变化，在NBM-mediated BLA内的突触作用可以与突触前神经元的改变相联系。 调节乙酰胆碱（ACh）合成和/或释放的机制。 另外，还将比较由以下因素诱发的3 H-ACh释放： 对照组杏仁核切片的电场刺激 和NGF治疗的大鼠，以直接确定是否用NGF治疗 导致发射器从NBM的终端容易地释放 胆碱能神经元 这些调查将在大脑中进行 取自年轻成年动物的切片和来自 不同衰老阶段的老年大鼠。 总体而言，拟议 研究的目的是提供一个全面的能力， 外源性NGF维持中枢胆碱能传递的条件 与衰老过程有关的胆碱能神经退化 并且其近似于在患有以下疾病的患者中发现的神经病理学特征： AD.

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.