NEUROPHYSIOLOGY OF A NOVEL DOPAMINERGIC SYSTEM

长期目标：表征生理学和突触 多巴胺能投射到胆碱能神经元的药理学 腹侧苍白球/无名质（VP/SI）。VP/SI是基础 调节复杂行为如认知的前脑结构， 奖励和目标导向的回应。含乙酰胆碱神经元 VP/SI被认为仲裁这些功能。近期解剖学 研究表明，VP/SI接受来自中脑多巴胺能神经的输入， 神经元然而，该系统的生理学尚未被研究。 假设：VP/SI胆碱能神经元受多巴胺能输入调节， 而这一输入是足够重要的，当删除， 胆碱能神经元改变它们的活性，并变得对 多巴胺能激动剂的作用。 具体目标： I：表征介导VP/SI的多巴胺受体亚型 多巴胺能神经纤维激活的神经元反应。电生理 VP/SI细胞对中脑多巴胺输入刺激的反应将是 研究了将确定这些反应是否可以通过以下方式减弱： 多巴胺能拮抗剂的微离子电渗应用， 特异于D1或D2受体亚型。 II：为了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。推测的胆碱能神经元 将对VP/SI进行电生理学表征。将确定 如果多巴胺能神经元的刺激也改变了这些神经元的反应， 细胞 III：确定是否破坏中脑含多巴胺的细胞 损害VP/SI胆碱能神经元的正常功能。的连续性 已知神经元输入对于脑细胞的正常功能至关重要。 实验将确定多巴胺能输入的丧失 降低VP/SI胆碱能神经元的通信能力。 胆碱能功能将在破坏前和破坏后进行定量。 多巴胺途径，通过测量1）乙酰胆碱周转率的变化，和2） 在电生理学上产生的灵敏度曲线的变化， VP/SI胆碱能神经元对多巴胺激动剂的反应。 这项工作将开创生理评估这一未探索 多巴胺投射结果将提供新的见解， 感知、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.