Dopamine modulation of the neostriatal feedback circuitry

GABA能抑制是新纹状体投射神经元活性的主要决定因素 有证据表明，这种抑制控制的很大一部分来自轴突侧支。 投射神经元本身。投射中功能性突触回路的存在 神经元在调节神经元活动的时空模式中起着关键作用。 新纹状体，特别是在控制活动平衡之间的功能隔离 新纹状体的输出通路(“直接”和“间接”通路)。扩大对…的理解 新纹状体投射神经元的抑制回路本提案的第一个目标将是 探讨纹状体之间突触通讯的连通性和生物物理特性。 黑质(直接)和纹状体-苍白球(间接)新纹状体投射神经元具有成对的全细胞电压和 急性脑片中的电流钳记录。 第二个主要目标是检验多巴胺调节突触传递的假设。 通过两种不同的受体机制，以电路依赖的方式在投射神经元之间传递。我们的 初步数据表明，投射神经元对的子集之间的突触传递 多巴胺通过DHike受体增强，而D2样受体抑制 互补的配对群体。考虑到这两种机制的严格分离 根据我们的初步数据，以及已知的多巴胺受体的投射路径选择性分布，我们 假设投射神经元的反馈回路参与多巴胺能神经系统的控制。 直接通路和间接通路通过对突触联系的不同调制而产生的相对活动 两条新纹状体输出通路的投射神经元。这些问题将在#年进行调查 从投影获得体外配对记录的电生理和药理学实验 用单细胞RT-PCR方法检测脑啡肽、P物质和5-羟色胺的表达 主要的多巴胺受体亚型。 负责对对手产量活性进行差异化调节的基本细胞机制 新纹状体的通路对于理解新纹状体的病理生理学具有重要的意义。 几种神经和精神疾病，包括帕金森氏症和亨廷顿病，精神分裂症 和吸毒成瘾。特别是，了解新纹状体回路的多巴胺能调制可能 促进识别新的、非多巴胺能的主要或辅助药物疗法 帕金森病，并有助于改善非药物治疗模式的帕金森 无序。

GABAergic inhibition is a primary determinant of the activity of neostriatal projection neurons and recent evidence demonstrates that a significant fraction of this inhibitory control originates from the axon collaterals of the projection neurons themselves. The existence of a functional synaptic circuitry among projection neurons suggests a critical role in the regulation of the spatial and temporal pattern of activity of the neostriatum, and in particular in the control of the balance of activity between the functionally segregated output pathways (the"direct" and "indirect" pathways) of the neostriatum. To extend the understanding of the inhibitory circuitry of neostriatal projection neurons the first objective of the present proposal will be to investigate the connectivity and the biophysical properties of synaptic communication between the striato- nigral (direct) and striato-pallidal (indirect) neostriatal projection neurons with paired whole cell voltage and current clamp recordings in acute brain slices . The second major objective is to test the hypothesis that dopamine regulates synaptic transmission among projection neurons in a circuit dependent manner through two different receptor mechanisms. Our preliminary data demonstrate that synaptic transmission between a subset of pairs of projection neurons is enhanced by dopamine through DHike receptors while D2-like receptors suppress transmission between a complementary population of pairs. Considering the strict segregation of the two mechanisms demonstrated by our preliminary data, and the known projection pathway selective distribution of dopamine receptors, we hypothesize that the feedback circuitry of projection neurons contributes to the dopaminergic control of the relative activity of the direct and indirect pathways through differential modulation of synaptic connections of projection neurons of the two neostriatal output pathways. These questions will be investigated in electrophysiological and pharmacological experiments by obtaining in vitro paired recordings from projection neurons identified using single-cell RT-PCR profiling of the expression of enkephalin, substance P and the 5 main dopamine receptor subtypes. The basic cellular mechanisms responsible for the differential regulation of activity of the opponent output pathways of the neostriatum has important implications for the understanding of the pathophysiology of several neurological and psychiatric disorders including Parkinson's and Huntington's disease, schizophrenia and drug addiction. In particular, understanding the dopaminergic modulation of the neostriatal circuitry may facilitate the identification of novel, non-dopaminergic primary or adjunctive pharmacotherapies of Parkinson's disease and contribute to the improvement of non-pharmacological treatment modalities of the disorder.