Anatomical and Physiological Characterization of the Thalamostriatal System

描述（由申请人提供）：由于临床数据显示中央/旁束（CM/PF）复合体的脑深部电刺激（DBS）（丘脑输入纹状体的主要来源）缓解了与抽动秽语综合征和帕金森病（PD）相关的症状，因此最近对丘脑纹状体系统产生了重大兴趣。然而，DBS的影响和CM/PF参与运动障碍的机制尚不清楚，因为缺乏对丘脑纹状体系统功能组织的了解。来自CM的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紧张性活性神经元[TAN]）。这些神经元的活动已被证明是调制在奖励任务在正常条件下，它已被证明，任务相关的活动被取消CM失活。异常TAN活性也可能是运动障碍的特征，例如肌张力障碍和PD。最近的研究结果表明，从我们的实验室和以前的啮齿动物的研究表明，电激活的纹状体神经元能CM传出经常导致抑制性TAN反应。兴奋性输入转化为抑制性反应的机制尚不清楚，但很可能涉及纹状体内GABA能加工。为了描绘参与介导非人灵长类动物纹状体胆碱能中间神经元对CM刺激的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能传递在调节灵长类壳核中TAN的自发和CM刺激诱导的神经元活动中的作用，以及（2）目的：明确猴纹状体胆碱能中间神经元体树突区沿着GABA能突触输入的微电路和化学表型。在第一组研究中，在纹状体记录位点附近微量注射GABA受体拮抗剂之前和之后，将在猴中记录TAN对CM电刺激的反应，以确定局部GABA能网络是否调节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。这些研究结果将有助于我们解剖灵长类动物中参与丘脑调节纹状体胆碱能中间神经元活性的神经元网络。这些结果也将有助于我们了解CM/PF DBS治疗运动障碍的机制。 公共卫生相关性：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，如帕金森病、图雷特综合征和疼痛。丘脑尾侧板内复合体（中央正中核/束旁核（CM/PF））的脑深部电刺激（DBS）可有效缓解与这些疾病相关的运动症状;然而，目前CM/PF DBS的应用有限，其治疗效果的解释受到有关丘脑纹状体系统功能的最小信息量的阻碍。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和功能关系，以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。

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.