Anatomical and Physiological Characterization of the Thalamostriatal System

描述（由申请人提供）：丘脑纹状体系统最近引起了极大的兴趣，因为临床数据显示，脑深部刺激（DBS）的中位/束旁（CM/PF）复合物，丘脑纹状体输入的主要来源，减轻了与图雷特综合征和帕金森病（PD）相关的症状。然而，由于对丘脑纹状体系统的功能组织缺乏了解，DBS的作用机制和CM/PF在运动障碍中的参与尚不清楚。其中一个来自CM的突触神经支配的主要目标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张力活跃神经元[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被调节，并且已被证明任务相关的活动被CM失活所取消。异常的TANs活动也可能是运动障碍的一个特征，如肌张力障碍和PD。我们实验室的最新发现和先前的啮齿动物研究表明，对纹状体的谷氨酸能CM传入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尚不清楚，但很可能涉及到纹状体内gaba能加工。为了描述参与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能传递在调节灵长类动物壳核中自发和cm刺激诱导的TANs神经元活动中的作用；(2)确定猴纹状体胆碱能中间神经元体树突结构域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受体拮抗剂前后，从电生理学上记录猴子的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gaba能调节TAN活性的底物。这些研究的发现将有助于我们剖析灵长类动物丘脑对纹状体胆碱能中间神经元活动的调节。这些结果也将有助于我们理解CM/PF DBS治疗运动障碍的潜在机制。

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.