Dopamine modulation of the neostriatal feedback circuitry

描述(申请人提供)：GABA能抑制是新纹状体投射神经元活性的主要决定因素，最近的证据表明，这种抑制控制的很大一部分来自投射神经元本身的轴突侧支。投射神经元之间功能性突触回路的存在表明，在调节新纹状体活动的空间和时间模式中，特别是在控制新纹状体功能分离的输出通路(直接通路和间接通路)之间的活动平衡方面，发挥着关键作用。为了加深对新纹状体投射神经元抑制回路的了解，本研究的第一个目的将是通过对急性脑片的全细胞电压和电流钳记录，研究纹状体-黑质(直接)和纹状体-苍白球(间接)新纹状体投射神经元之间的连接和突触通讯的生物物理特性。第二个主要目的是验证多巴胺通过两种不同的受体机制以电路依赖的方式调节投射神经元之间突触传递的假设。我们的初步数据表明，多巴胺通过D1样受体促进了一对投射神经元之间的突触传递，而D2样受体抑制了互补的一对投射神经元之间的传递。考虑到我们的初步数据显示这两种机制的严格分离，以及已知的多巴胺受体的投射通路选择性分布，我们假设投射神经元的反馈电路通过对两条新纹状体输出通路的投射神经元的突触联系的不同调制来参与对直接和间接通路的相对活动的多巴胺能控制。这些问题将在电生理学和药理学实验中进行研究，方法是从投射神经元获得体外配对记录，使用单细胞RT-PCR分析脑啡肽、P物质和5种主要多巴胺受体亚型的表达。负责调节新纹状体输出通路活动的基本细胞机制对于理解帕金森氏病、亨廷顿病、精神分裂症和药物成瘾等多种神经和精神疾病的病理生理学具有重要意义。特别是，了解新纹状体回路的多巴胺能调制可能有助于识别帕金森病的新的非多巴胺能初级或辅助药物治疗，并有助于改善该疾病的非药物治疗方式。

DESCRIPTION (provided by applicant): 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 D1-like 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.