Anatomical and Physiological Characterization of the Thalamostriatal System

丘纹状体系统的解剖学和生理学特征

• 批准号: 7913985
• 负责人: Kalynda Kari Gonzales
• 金额: $ 3.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913985
• 关键词: Basal Ganglia; Chemicals; Clinical Data; Complex; Corpus striatum structure; Deep Brain Stimulation; Dystonia; Functional disorder; GABA Antagonists; Gilles de la Tourette syndrome; Glutamates; Individual; Interneurons; Knowledge; Laboratories; Mediating; Microinjections; Monkeys; Motor; Movement Disorders; Neurons; Pain; Parafascicular Nucleus; Parkinson Disease; Phenotype; Physiological; Primates; Process; Regulation; Rewards; Rodent; Role; Site; Source; Symptoms; Synapses; System; Thalamic structure; Therapeutic Effect; Translating; cholinergic; insight; interest; nerve supply; nonhuman primate; public health relevance; putamen; response; transmission process

DESCRIPTION (provided by applicant): The thalamostriatal system has generated significant interest recently because of clinical data showing that deep brain stimulation (DBS) of the centromedian/parafascicular (CM/PF) complex, the main sources of thalamic inputs to the striatum, alleviates symptoms associated with Tourette syndrome and Parkinson's disease (PD). However, the mechanisms underlying the effects of DBS and the involvement of CM/PF in movement disorders are not understood, due to lack of knowledge on the functional organization of the thalamostriatal system. One of the principal targets of synaptic innervation from the CM is the group of striatal cholinergic interneurons (likely corresponding to tonically active neurons [TANs] in electrophysiological studies). The activity of these neurons has been shown to be modulated in rewarded tasks under normal conditions, and it has been shown that the task-related activity is abolished by CM inactivation. Abnormal TANs activity may also be a feature of movement disorders, such as dystonia and PD. Recent findings from our laboratory and previous rodent studies have demonstrated that electrical activation of the glutamatergic CM efferents to the striatum frequently results in inhibitory TAN responses. The mechanisms involved in translating the excitatory inputs into inhibitory responses remain unknown, but it is likely that intrastriatal GABAergic processing is involved. To delineate the neuronal microcircuits involved in mediating the responses of striatal cholinergic interneurons to CM stimulation in nonhuman primates, two specific aims are proposed: (1) To determine the role of GABAergic transmission intrinsic to the striatum in regulating the spontaneous and CM-stimulation induced neuronal activity in TANs in the primate putamen and (2) To define the microcircuitry and chemical phenotype of GABAergic synaptic inputs along the somatodendritic domain of striatal cholinergic interneurons in monkeys. In the first set of studies, the responses of TANs to electrical CM stimulation will be recorded electrophysiologically in monkeys, before and after microinjections of GABA receptor antagonists in the vicinity of the striatal recording sites to determine if local GABAergic networks are modulating the responses of TANs to CM activation. In the second set of studies, a quantitative ultrastructural analysis of the GABAergic synaptic innervation of individual striatal cholinergic interneurons will be performed, providing insights into the substrate that underlies the GABAergic modulation of TAN activity. The findings from these studies will help us to dissect the neuronal networks that are involved in the thalamic regulation of the activity of striatal cholinergic interneurons in primates. The results will also be relevant for our understanding of the mechanisms underlying the therapeutic effects of CM/PF DBS in movement disorders. PUBLIC HEALTH RELEVANCE: The interaction between the thalamus and the striatum has been implicated in disturbances of basal ganglia function such as Parkinson's disease, Tourette syndrome, and pain. Deep brain stimulation (DBS) of the thalamic caudal intralaminar complex, the centromedian/parafascicular nuclei (CM/PF), is effective in relieving motor symptoms associated with these conditions; however, the current application of CM/PF DBS is limited and the interpretation of its therapeutic effects is hampered by the minimal amount of information about the function of the thalamostriatal system. This study aims to examine in detail the anatomical and functional relationship between the CM/PF complex and the striatum in nonhuman primates, in order to gain a better understanding of the involvement of the thalamostriatal system in basal ganglia dysfunction and movement disorders.

描述（由申请人提供）：丘脑纹状体系统最近引起了人们的极大兴趣，因为临床数据表明，对纹状体丘脑输入的主要来源——中心正中/束旁（CM/PF）复合体进行深部脑刺激（DBS）可以减轻抽动秽语综合征和帕金森病（PD）相关的症状。然而，由于缺乏对丘脑纹状体系统功能组织的了解，DBS 的作用以及 CM/PF 参与运动障碍的机制尚不清楚。 CM 突触神经支配的主要目标之一是纹状体胆碱能中间神经元组（可能对应于电生理学研究中的强直活性神经元 [TAN]）。这些神经元的活动已被证明在正常条件下的奖励任务中受到调节，并且已表明与任务相关的活动被 CM 失活所消除。 TAN 活性异常也可能是运动障碍的一个特征，例如肌张力障碍和 PD。我们实验室的最新发现和之前的啮齿动物研究表明，纹状体谷氨酸能 CM 传出神经的电激活经常导致抑制性 TAN 反应。将兴奋性输入转化为抑制性反应的机制仍然未知，但很可能涉及纹状体内 GABA 能处理。为了描绘非人类灵长类动物中介导纹状体胆碱能中间神经元对 CM 刺激反应的神经元微电路，提出了两个具体目标：（1）确定纹状体固有的 GABA 能传输在调节灵长类壳核 TAN 中自发和 CM 刺激诱导的神经元活动中的作用；（2）定义 猴子纹状体胆碱能中间神经元体细胞树突域 GABA 能突触输入的微电路和化学表型。在第一组研究中，将在纹状体记录位点附近显微注射 GABA 受体拮抗剂之前和之后，在猴子中通过电生理学记录 TAN 对电 CM 刺激的反应，以确定局部 GABA 能网络是否正在调节 TAN 对 CM 激活的反应。在第二组研究中，将对单个纹状体胆碱能中间神经元的 GABA 能突触神经支配进行定量超微结构分析，从而深入了解 TAN 活性的 GABA 能调节的底物。这些研究的结果将帮助我们剖析参与灵长类动物纹状体胆碱能中间神经元活动的丘脑调节的神经元网络。这些结果也将有助于我们理解 CM/PF DBS 对运动障碍的治疗作用的潜在机制。 公共健康相关性：丘脑和纹状体之间的相互作用与基底神经节功能紊乱有关，例如帕金森病、抽动秽语综合征和疼痛。对丘脑尾部层内复合体、中心正中/束旁核（CM/PF）进行深部脑刺激（DBS）可有效缓解与这些病症相关的运动症状；然而，目前 CM/PF DBS 的应用有限，并且有关丘脑纹状体系统功能的信息量极少，阻碍了对其治疗效果的解释。本研究旨在详细研究非人灵长类动物 CM/PF 复合体与纹状体之间的解剖学和功能关系，以便更好地了解丘脑纹状体系统在基底神经节功能障碍和运动障碍中的参与。