Thalamic interactions with the striatum

描述（由申请人提供）：帕金森病的运动功能障碍通常被描述为基底节区-丘脑皮质回路活动改变的结果。然而，最近的研究表明，丘脑纹状体投射的异质家族也可能受到疾病的强烈影响，这些变化可能有助于帕金森病体征和症状的发展。最主要的丘脑纹状体投射来自丘脑尾侧的层间核（中央核和束旁核[CM/Pf]）。CM/ pf纹状体投射产生轴突终末簇，优先靶向纹状体投射神经的树突轴，以及胆碱能中间神经元。这种投射可能在奖励信息的处理和警惕性和注意力的调节中起重要作用。丘脑纹状体纤维的另一个主要来源是基底神经节接收腹前核（VA）和腹外侧核（VL）。这些核中的神经元向纹状体发送长未分枝的轴突，具有许多过路型的变异。v -纹状体突起对纹状体功能的影响尚不清楚。对帕金森病患者脑组织的死后分析表明，丘脑纹状体投射的源核及其在纹状体中的突触组织受到神经退行性过程的强烈影响。CM/Pf中的神经元受到的影响尤其严重，超过50%的神经元在病程早期发生变性。我们已经证明，神经元丧失的这些方面在mptp治疗的（帕金森病）猴子身上得到了忠实的复制，同时丘脑纹状体终末也相应减少。此外，纹状体中树突棘的形态和密度也发生了广泛的变化，纹状体是VL输入的主要接受者。这些变化对纹状体活动的功能影响尚不清楚，但可能是实质性的，并且考虑到解剖和病理差异，两种投射系统之间可能存在差异。我们建议通过对猴子的功能和解剖学研究来验证这一假设。功能研究（目标1）将利用光遗传学方法，使我们能够选择性地激活cm -纹状体或v -纹状体投射的末端，并检查对清醒灵长类动物纹状体投射神经元和胆碱能中间神经元活性的影响。这些研究将首先在正常状态下进行，然后在动物被MPTP治疗后呈现帕金森病后再次进行。功能研究将在相同动物的定量电镜分析中得到补充，其中视蛋白表达将被用作解剖标记物，以确定CM-或vl纹状体末端突触后靶点的帕金森相关变化（目的2）。本研究将有助于我们更全面地了解帕金森病的回路病理生理，并为通过影响特定的丘脑纹状体相互作用来治疗帕金森病的治疗策略的发展奠定基础。

DESCRIPTION (provided by applicant): The motor dysfunction of Parkinson's disease is usually described as the result of changes in the activity of basal ganglia-thalamocortical circuits. However, recent research has shown that the heterogeneous family of thalamostriatal projections may also be strongly affected by the disease, and that these changes may contribute to the development of parkinsonian signs and symptoms. The most substantial thalamostriatal projection comes from the caudal intralaminar nuclei in the thalamus (the centromedian and parafascicular nuclei [CM/Pf]). The CM/Pf-striatal projection gives rise to clusters of axon terminals that target preferentially dendritic shafts of striatal projection neuros, as well as cholinergic interneurons. This projection may be prominently involved in the processing of reward information and in the regulation of vigilance and attention. Another major source of thalamostriatal fibers are the 'basal ganglia receiving' ventral anterior (VA) and ventrolateral (VL) nuclei. Neurons in these nuclei send long un-branched axons to the striatum, with many en passant-type varicosities. The impact of the VL-striatal projections on striatal function is unknown. Postmortem analysis of brain tissue from parkinsonian patients has demonstrated that the source nuclei of the thalamostriatal projection and the organization of their synapses in the striatum are strongly affected by the neurodegenerative process. Neurons in the CM/Pf are particularly affected, with degeneration of more than 50% of neurons early in the course of the disease. We have demonstrated that these aspects of neuron loss are faithfully replicated in MPTP-treated (parkinsonian) monkeys, along with a corresponding decrease in thalamostriatal terminals. In addition, there are extensive changes in the morphology and density of dendritic spines in the striatum, which are the primary recipients of VL input. The functional impact of these changes on striatal activity is not known, but is likely t be substantial, and, given the anatomical and pathological differences, may differ between the two projection systems. We propose to test this hypothesis with a combination of functional and anatomical studies in monkeys. The functional studies (aim 1) will make use of an optogenetic approach that will allow us to selectively activate terminals of the CM-striatal or VL-striatal projections, and to examine the resulting effects on the activity of striatal projection neurons an cholinergic interneurons in awake primates. These studies will first be done in the normal state, and then again after the animals have been rendered parkinsonian by treatment with MPTP. The functional studies will be complemented with quantitative electron microscopic analyses in the same animals, in which opsin expression will be used as an anatomic marker to identify parkinsonism-related changes in the postsynaptic targets of CM- or VL-striatal terminals (aim 2). The proposed studies will help us to gain a more complete understanding of the circuit pathophysiology of parkinsonism, and set the stage for the development of therapeutic strategies to treat Parkinson's disease through influencing specific thalamostriatal interactions.