Thalamic interactions with the striatum

丘脑与纹状体的相互作用

• 批准号: 9266495
• 负责人: Thomas N Wichmann
• 金额: $ 39.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266495
• 关键词: Affect; Anatomy; Animals; Anterior; Attention; Autopsy; Axon; Basal Ganglia; Behavior; Brain; Cell Nucleus; Centromedian Thalamic Nucleus; Cognitive; Complement; Corpus striatum structure; Dendritic Spines; Development; Disease; Dopamine; Electrons; Family; Fiber; Functional disorder; Interneurons; Intralaminar Nuclear Group; Investigation; Lead; Light; Methods; Microscopic; Monkeys; Morphology; Nerve Degeneration; Neurons; Opsin; Output; Parafascicular Nucleus; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Pattern; Population; Presynaptic Terminals; Primates; Process; Regulation; Reporting; Research; Research Personnel; Rewards; Rodent; Role; Signs and Symptoms; Site; Source; Structure; Synapses; System; Techniques; Testing; Thalamic structure; Time; Varicosity; Ventral Lateral Thalamic Nucleus; animal tissue; awake; brain tissue; cholinergic; cholinergic neuron; density; experimental study; in vivo; information processing; motor disorder; neuron loss; novel therapeutic intervention; optogenetics; postsynaptic; public health relevance; putamen; reward processing; therapeutic development; tool; transmission process; vigilance; viral gene delivery

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.

描述(申请人提供)：帕金森氏病的运动功能障碍通常被描述为基底节-丘脑皮质回路活动改变的结果。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这种疾病的强烈影响，这些变化可能有助于帕金森氏症的症状和体征的发展。最重要的丘脑纹状体投射来自丘脑的尾侧板内核(中央正中核和束旁核[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。这种投射可能显著地参与奖赏信息的处理以及警觉和注意的调节。丘脑纹状体纤维的另一个主要来源是接受腹前核(VA)和腹外核(VL)的“基底节”。这些核团中的神经元向纹状体发送长的不分叉的轴突，其中有许多传递型曲张。VL-纹状体投射对纹状体功能的影响尚不清楚。帕金森病患者脑组织的尸检分析表明，丘脑-纹状体投射的来源核及其在纹状体中的突触组织受到神经退变过程的强烈影响。CM/PF中的神经元受影响尤其严重，50%以上的神经元在病程早期变性。我们已经证明，在MPTP治疗(帕金森病)猴子身上，神经元丢失的这些方面都得到了忠实的复制，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，它们是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，但很可能是实质性的，考虑到解剖和病理上的差异，这两个投影系统可能会有所不同。我们建议通过对猴子的功能和解剖学研究相结合的方式来验证这一假设。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VL-纹状体投射的终末，并检查由此产生的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动的影响。这些研究将首先在正常状态下进行，然后在动物通过MPTP治疗而患上帕金森病后再次进行。这些功能研究将与同一动物的定量电子显微镜分析相辅相成，在这些动物中，视蛋白的表达将被用作解剖学标记，以确定CM或VL纹状体终末突触后靶的帕金森相关变化(目标2)。这些研究将帮助我们更全面地了解帕金森氏症的回路病理生理学，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制定奠定基础。