Anatomical and Physiological Characterization of the Thalamostriatal System

描述(申请人提供)：丘脑纹状体系统最近引起了极大的兴趣，因为临床数据表明，中央正中/束旁(CM/PF)复合体的脑深部刺激(DBS)是丘脑输入纹状体的主要来源，可以缓解与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的作用和CM/PF参与运动障碍的潜在机制尚不清楚。来自CM的突触神经支配的主要靶点之一是纹状体胆碱能中间神经元群(在电生理学研究中很可能对应于紧张性活动神经元[TANS])。在正常情况下，这些神经元的活动被证明在奖赏任务中受到调节，并且已经被证明任务相关的活动被CM失活所消除。日光浴活动异常也可能是运动障碍的一个特征，如肌张力障碍和帕金森病。我们实验室和以前的啮齿动物研究的最新发现表明，谷氨酸能CM传出到纹状体的电激活经常导致抑制TAN反应。将兴奋性输入转化为抑制性反应的机制尚不清楚，但很可能涉及纹状体内的GABA能处理。为了阐明参与调节非人灵长类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TAN自发和CM刺激诱发神经元活动中的作用；(2)确定GABA能突触输入沿猕猴纹状体胆碱能中间神经元的躯体树突域的微电路和化学表型。在第一组研究中，在纹状体记录部位附近微量注射GABA受体拮抗剂之前和之后，将在猴子身上记录TANS对CM电刺激的反应，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的超微结构分析，以深入了解GABA能调节TAN活动的底物。这些研究的发现将有助于我们解剖参与丘脑调节灵长类纹状体胆碱能中间神经元活动的神经元网络。这一结果也将有助于我们理解CM/PF DBS对运动障碍的治疗效果的潜在机制。 公共卫生相关性：丘脑和纹状体之间的相互作用与基底节功能障碍有关，如帕金森氏病、多发性抽动症和疼痛。丘脑尾侧板内复合体中央正中/束旁核(CM/PF)的深部脑刺激(DBS)在缓解与这些疾病相关的运动症状方面是有效的；然而，CM/PF DBS目前的应用有限，其疗效的解释受到关于丘脑纹状体系统功能的最少信息量的阻碍。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，以期更好地了解丘脑-纹状体系统在基底节功能障碍和运动障碍中的作用。

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.