Nigrostriatal dopamine function

基底神经节是控制自主运动的中枢回路的重要组成部分。 以及感觉运动整合、运动和非运动学习，以及一些更高的认知功能。 基底节的主要输入结构是纹状体，主要由中等大小的GABA能 棘突投射神经元占啮齿动物纹状体神经元的95%。剩下的神经元由 胆碱能中间神经元和3种类型的GABA能中间神经元。GABA能中间神经元起着至关重要的作用 通过参与影响棘波的强大前馈抑制回路，在纹状体功能中发挥作用 刺状神经元的计时。多巴胺(DA)起源于黑质，长期以来一直被认为是 在纹状体功能中起着至关重要的作用，黑质纹状体DAR能通路的退化是 帕金森病的病因S病是一种进行性的、无法治愈的疾病，影响着100到150万人 美国人。 最近，一种新型的纹状体神经元在包括人类在内的各种物种中被发现。 该神经元表达酪氨酸羟化酶(TH)，这是DA合成中的限速酶，也是一种可靠的 中脑DA神经元的标志物。在灵长类动物中，基本上所有这些神经元也表达DA 转运蛋白(DAT)强烈提示它们是DAR能的。这些神经元还表达谷氨酸脱羧酶， 负责合成GABA的酶，也是GABA能的共同标志 神经元。在实验性DA后，这些神经元的数量在所有物种中都增加了几倍 失神经，其中一些细胞表达L氨基酸脱羧酶和 囊泡单胺转运体(VMAT)。这些神经元可能代表了一种迄今未被认识到的来源 纹状体DA的表达和特发性帕金森病患者DA丢失的一个潜在的有用补偿来源--S 也是治疗该病的新治疗方法的潜在目标。 然而，对这些神经元的电生理特性几乎一无所知，因为 没有发表过关于他们录音的报道。同样，也没有关于它们传出或传入突触的数据 连通性，甚至它们是否释放DA和/或GABA。小鼠纹状体切片的遗传学应用 在TH启动子的控制下进行绿色荧光蛋白(EGFP)的工程表达 在体外对这些神经元进行视觉引导记录。使用这些小鼠，无论是未经治疗的还是在单侧 多巴胺能去神经和/或L-多巴替代疗法，我们将描述基本的电生理学 纹状体DA神经元的特性、传入和传出连接、DA的代偿性变化 PD耗竭动物模型及其在纹状体DA和GABA能神经传递中的作用。此外, 这些小鼠为研究新种群的电生理和解剖学特性提供了一种新的方法 以前很难或不可能研究的纹状体中间神经元。

The basal ganglia is a an essential component of the central circuitry controlling voluntary movement as well as sensorimotor integration, motor and non-motor learning, and a number of higher cognitive functions. The major input structure of the basal ganglia is the striatum, comprised mostly of medium sized GABAergic spiny projection neurons which make up 95% of striatal neurons in the rodent. The remaining neurons consist of cholinergic interneurons and 3 types of GABAergic interneurons. The GABAergic interneurons play a crucial role in striatal function by participating in a powerful feedforward inhibitory circuit that affects spike timing in the spiny neurons. Dopamine (DA), originating in the substantia nigra, has long been recognized to play an essential role in striatal function, and it is the degeneration of the nigrostriatal DAergic pathway that is the cause of Parkinson¿s disease, a progressive and incurable disorder that affects between 1 and 1.5 million Americans. Recently a novel type of striatal neuron has been recognized in a variety of species including humans. This neuron expresses tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA and a reliable marker for DA neurons in the midbrain. In primates essentially all of these neurons also express the DA transporter (DAT) suggesting strongly that they are DAergic. These neurons also express glutamate decarboxylase, the enzyme responsible for the synthesis of GABA and a common marker for GABAergic neurons. The numbers of these neurons increases several-fold in all species following experimental DA denervation, and some of them have been shown to express L-amino acid decarboxylase (AADC) and the vesicular monoamine transporter (VMAT). These neurons could represent a heretofore-unappreciated source of striatal DA and a potentially useful source of compensation for DA loss in idiopathic Parkinson¿s disease as well as a potential target for novel therapeutic approaches to the treatment of the disease. However, virtually nothing is known about the electrophysiological properties of these neurons, as there are no published reports of recordings from them. Similarly, there are no data on their efferent or afferent synaptic connectivity, or even whether they release DA and/or GABA. The use of striatal slices from mice genetically engineered to express green fluorescent protein (EGFP) under the control of the TH promotor allows visually guided recording from these neurons in vitro. Using these mice, both untreated and after unilateral dopaminergic denervation and/or L-DOPA replacement therapy, we will describe the basic electrophysiological properties of striatal DA neurons, their afferent and efferent connectivity, compensatory changes in DA depletion animal models of PD, and their role in striatal DA and GABAergic neurotransmission. In addition, these mice afford a novel way to study the electrophysiological and anatomical properties of novel populations of striatal interneurons that have been very difficult or impossible to study previously.