NEUROPHYSIOLOGY OF A NOVEL DOPAMINERGIC SYSTEM

长期目标：描述生理和突触的特征 多巴胺能投射至胆碱能神经元的药理学研究 腹侧苍白球/无名质(VP/SI)。VP/SI是一个基本的 前脑结构，它调节复杂的行为，如认知， 奖励，以目标为导向的回应。下丘脑乙酰胆碱能神经元 VP/SI被认为对这些功能进行了仲裁。现代解剖学 研究表明，VP/SI接受中脑多巴胺能传入 神经元。然而，这个系统的生理学还没有被研究过。 假设：VP/SI胆碱能神经元受多巴胺能输入的调节， 并且该输入具有足够的重要性，当移除时， 胆碱能神经元改变其活动，并对 多巴胺能激动剂的作用。 具体目标： I：研究介导VP/SI的多巴胺受体亚型 神经元对多巴胺能纤维激活的反应。电生理学 Vp/SI细胞对刺激中脑多巴胺输入的反应将是 学习。将确定这些反应是否可以通过以下方式衰减 多巴胺能拮抗剂的微离子电泳法应用 D1或D2受体亚型的特异性。 II：确定中脑多巴胺能投射是否调节 含乙酰胆碱的VP/SI神经元。脑内胆碱能神经元的推测 将对VP/SI进行电生理学表征。这将是确定的 如果刺激多巴胺能神经元也会改变这些神经元的反应 细胞。 III：确定破坏中脑多巴胺细胞是否 损害VP/SI胆碱能神经元的正常功能。的连续性 众所周知，神经元输入对脑细胞的正常功能至关重要。 实验将确定多巴胺能输入的损失 降低VP/SI胆碱能神经元的通讯能力。 胆碱能功能将在破坏前后进行量化 通过测量1)乙酰胆碱周转率的变化和2)多巴胺途径 电生理学产生的灵敏度曲线的移动 VP/SI胆碱能神经元对多巴胺激动剂的反应。 这项工作将开创对这一未被探索的 多巴胺投射。结果将提供理解的新视角 知觉、认知和运动功能障碍的异常精神状态 同时存在。

LONG-TERM OBJECTIVE: To characterize the physiology and synaptic pharmacology of the dopaminergic projection to cholinergic neurons of the ventral pallidum/substantia innominata (VP/SI). The VP/SI is a basal forebrain structure which mediates complex behaviors such as cognition, reward, and goal-oriented responding. Acetylcholine-containing neurons of the VP/SI are thought to arbitrate these functions. Recent anatomical studies reveal that the VP/SI receives inputs from midbrain dopaminergic neurons. However, the physiology of this system has not been investigated. HYPOTHESIS: VP/SI cholinergic neurons are regulated by dopaminergic inputs, and this input is of sufficient importance that, when removed, the cholinergic neurons alter their activity and become supersensitive to the actions of dopaminergic agonists. SPECIFIC AIMS: I: To characterize the dopamine receptor subtype which mediates VP/SI neuronal responses to activation of dopaminergic fibers. Electrophysiologic responses by VP/SI cells to stimulation of midbrain dopamine inputs will be studied. It will be determined if these responses can be attenuated by microiontophoretic application of dopaminergic antagonists which are specific for the D1 or D2 receptor subtype. II: To determine if midbrain dopaminergic projections regulate acetylcholine-containing VP/SI neurons. Putative cholinergic neurons of the VP/SI will be electrophysiologically characterized. It will be determined if stimulation of dopaminergic neurons also alter the responses of these cells. III: To determine if destruction of midbrain dopamine-containing cells impairs normal function of VP/SI cholinergic neurons. Continuity of neuronal inputs is known to be vital for normal function of brain cells. Experiments will determine whether loss of the dopaminergic input diminishes the ability of VP/SI cholinergic neurons to communicate. Cholinergic function will be quantified before and after destruction of dopamine pathways by measuring 1) changes in acetylcholine turnover, and 2) shifts in the sensitivity curve generated electrophysiologically for the VP/SI cholinergic neuronal response to dopamine agonists. This work will pioneer physiological evaluations of this unexplored dopamine projection. Results will provide new insight towards understanding abnormal mental states where perceptive, cognitive and motor dysfunctions exist simultaneously.