AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

这项拟议中的研究的目标是了解大脑底部的大脑 (BF)的组织是为了调节分布在 大脑皮层的感觉、运动和高级认知系统。 药理研究表明，多巴胺能和谷氨酸能 刺激对皮质乙酰胆碱的释放有深远的影响， 这表明这些传入细胞在调节 注意、唤醒和奖励行为状态下的胆碱能音 机械装置。拟议中的实验将测试各种假设 大脑皮层胆碱能及相关的非胆碱能途径 特定基底前脑环路中的神经元受 多巴胺能和谷氨酸能传入。 将检验以下具体假设：1)前额叶 谷氨酸能轴突终止于不同类型的GABA能神经元 基底前脑。2)不同类型的BF-GABA能神经元。 通过存在不同的钙结合蛋白(即， 小白蛋白，Calbindin D28，calretinin)，收缩BF胆碱能 投射神经元。突触的数量和形态 胆碱能神经元将根据位置和/或类型的不同而变化 GABA能神经元。3)谷氨酸和多巴胺影响胆碱能 通过不同的突触前和突触后机制输出神经元。 为了实现这些目标，我们将结合解剖学和 电生理学研究。以下是主要的研究方向 追查：1)查明终止的来源和地点 基底前脑神经元上的多巴胺能和谷氨酸能终末。2) 电针刺激效应的电生理特征 BF黑质或推测的谷氨酸能来源 神经元，在活体细胞外记录。3)生物细胞因子的重建 BF-GABA能神经元与胆碱能突触的标记 神经元。4)多巴胺能和谷氨酸能的细胞特性 感受器。这些研究将通过使用活体细胞旁辅助 传入通路的记录、顺行追踪和双重 在光和光的不同组合的免疫标记方法 电子显微镜水平，辅以计算机化的3-D 重建已识别的神经元及其突触。

The goal of the proposed research is to understand how the basal foebrain (BF) is organized to modulate distributed neuronal processes within sensory, motor and higher order cognitive systems in the cerebral cortex. Pharmacological studies have shown that dopaminergic and glutamatergic stimulation have a profound effect on cortical acetylcholine release, suggesting a critical role for these afferents in mediating increased cholinergic tone in behavioral states of attention, arousal and reward mechanisms. The proposed experiments will test various hypotheses about the ways in which corticipetal cholinergic and associated non-cholinergic neurons in specific basal forebrain circuits are influenced by dopaminergic and glutamatergic afferents. The following specific hypothesis will be tested: 1) Prefrontal glutamatergic axons terminate on different type of GABAergic neurons in the basal forebrain. 2) Different types of BF GABAergic neurons, identified by the presence of different calcium binding proteins (i.e., parvalbumin, calbindin D28, calretinin), contract BF cholinergic projection neurons. The number of and topography of synapses on the cholinergic neurons will vary according to the location and/or the type of GABAergic neuron. 3) Glutamate and dopamine influence the cholinergic output neurons through different pre- and postsynaptic mechanisms. To accomplish these goals e will undertake on a combined anatomical and electrophysiological study. The following major lines of research will be pursued: 1) Identification of the sources and site of termination of dopaminergic and glutamatergic terminals on basal forebrain neurons. 2) Electrophysiological characterization of thee effect of the stimulation of the substantia nigra or putative glutamatergic sources on identified BF neurons, recorded extracellularly in vivo. 3) Reconstruction of biocytin labeled BF GABAergic neurons to identify their synapses with cholinergic neurons. 4) Cellular characterization of dopaminergic and glutamatergic receptors. These studies will be aided by using in vivo juxtacellular recording, anterograde tracing of afferent pathways and double immunolabeling methods in various combinations at both the light and electron microscopic level, supplemented by computerized 3-D reconstruction of identified neurons and their synapses.