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-丘脑皮质回路活动变化的结果。然而，最近的研究表明，丘脑纹状体投射的异质性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。最重要的丘脑纹状体投射来自丘脑尾侧板内核（中央核和束旁核[CM/Pf]）。CM/PF-纹状体投射产生轴突终末簇，其优先靶向纹状体投射神经元的树突轴以及胆碱能中间神经元。这种投射可能显著地参与奖赏信息的处理以及警惕性和注意力的调节。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（VA）和腹外侧（VL）核。这些核团中的神经元向纹状体发送长的不分支的轴突，具有许多过路型静脉曲张。VL-纹状体投射对纹状体功能的影响尚不清楚。对帕金森病患者脑组织的尸检分析表明，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中的神经元特别受影响，在疾病过程的早期超过50%的神经元变性。我们已经证明，这些方面的神经元损失忠实地复制MPTP治疗（帕金森病）猴，沿着相应的减少丘脑纹状体终端。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，但很可能不是实质性的，并且考虑到解剖学和病理学差异，可能在两个投射系统之间存在差异。我们建议测试这一假设的功能和解剖学研究相结合的猴子。功能研究（目标1）将利用光遗传学方法，使我们能够选择性激活CM-纹状体或VL-纹状体投射的末端，并检查对纹状体投射神经元和胆碱能中间神经元活动的影响。清醒灵长类动物。这些研究将首先在正常状态下进行，然后在通过MPTP治疗使动物患帕金森病后再次进行。在相同动物中，将通过定量电子显微镜分析补充功能研究，其中视蛋白表达将用作解剖学标记物，以识别CM-或VL-纹状体终末突触后靶点中的帕金森病相关变化（目的2）。拟议的研究将帮助我们获得更全面的了解帕金森氏症的电路病理生理学，并设置阶段的治疗策略，通过影响特定的丘脑纹状体的相互作用来治疗帕金森氏病的发展。

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.