Dopamine modulation of the neostriatal feedback circuitry

GABA能抑制是新纹状体投射神经元活动的主要决定因素， 有证据表明，这种抑制性控制的重要部分来自轴突侧支 投射神经元本身。投射之间存在功能性突触回路 神经元的活动的空间和时间模式的调节中起着关键作用， 新纹状体，特别是在控制活动之间的平衡功能分离 新纹状体的输出通路（“直接”和“间接”通路）。扩展对…的理解 新纹状体投射神经元的抑制回路本提议的第一个目标将是 研究纹状体之间突触通讯的连接性和生物物理特性， 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， 电流钳记录急性脑切片。 第二个主要目的是检验多巴胺调节突触传递的假说 在投射神经元中以回路依赖的方式通过两种不同的受体机制。我们 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样受体抑制多巴胺和多巴胺之间的传递。 配对的互补种群。考虑到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途径选择性分布，我们 假设投射神经元的反馈回路有助于多巴胺能控制 直接和间接途径的相对活性通过突触连接的差异调节， 两条新纹状体输出通路的投射神经元。这些问题将在 通过从投射获得体外成对记录的电生理学和药理学实验 使用脑啡肽、P物质和5-羟色胺的表达的单细胞RT-PCR谱鉴定神经元。 主要的多巴胺受体亚型 负责对手输出活动差异调节的基本细胞机制 新纹状体的通路对于理解脑卒中的病理生理学具有重要意义。 几种神经和精神疾病，包括帕金森病和亨廷顿病、精神分裂症 和毒瘾特别是，了解新纹状体回路的多巴胺能调节可能 促进识别新的、非多巴胺能的主要或连续的药物治疗， 帕金森氏病的非药物治疗方式的改善， disorder.

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.