Cortical connections with the limbic territory of the basal ganglia

描述(由申请人提供)：越来越多的证据表明，基底节(BG)参与了多个分离的“环”，皮质区域广泛，包括运动区、前额叶、顶叶后区和颞下皮质。这些回路可以为大脑皮层提供神经基础，以影响行为的运动、认知、情感和知觉领域。我们和其他人认为，大脑皮质BG环路的异常活动不仅会导致运动障碍，还会导致非运动症状，如与强迫症(OCD)和抽动症(TS)相关的症状。我们实验的总体目标是将与BG功能障碍相关的一些非运动症状与负责它们表达的皮质区域联系起来。基底节分为感觉运动区、联合区和边缘区。这些细分是基于解剖联系和免疫组织化学染色模式。这个应用程序将重点放在边缘区域。先前的研究表明，将GABA拮抗剂荷包牡丹碱(Bicuculline，Bic)微量注射到苍白球(GPE)外段的边缘区域会引起异常行为，包括过度梳理、咬指甲和交流手势。我们将使用狂犬病病毒的跨神经元传输来确定与GPE中Bic产生这些行为的部位相互连接的皮质区域。我们提出了两组实验。首先，我们将使用Bic微量注射从行为上确定GPE边缘区域的特定部位。然后，我们将狂犬病病毒注射到GPE中，并允许逆行跨神经元运输到大脑皮层的二级神经元。这种方法将识别为GPE的边缘区域提供输入的皮质神经元。在第二组实验中，我们将再次使用Bic注射来确定GPE边缘区域的特定位置。这些部位应以微小病变为标志。然后，我们将把狂犬病病毒注射到大脑皮层感兴趣的部位。在第一组实验中，这些部位将是标记神经元密度最高的部位。我们将允许逆行跨神经元运输到GPE中的三级神经元。我们将把这些GPE神经元的位置与GPE部位的标记损伤进行比较。这种方法将确定GPE中作为边缘区域输出目标的皮质区域。总之，这些实验应该为导致基底节功能障碍的非运动性症状的皮质区域提供新的见解。这些信息可能会为治疗强迫症和TS等复杂疾病开辟新的途径。

DESCRIPTION (provided by applicant): There is growing evidence that the basal ganglia (BG) participate in multiple segregated "loops" with a wide variety of cortical areas including regions of motor, prefrontal, posterior parietal and inferotemporal cortex. These circuits could provide the BG with the neural substrate to influence motor, cognitive, emotional and perceptual domains of behavior. We and others have argued that abnormal activity in BG loops with the cerebral cortex could lead not only to motor disorders, but also to non-motor symptoms like those associated with Obsessive-Compulsive Disorder (OCD) and Tourette Syndrome (TS). The overall goal of our experiments is to link some of the non-motor symptoms associated with BG dysfunction to the cortical areas that are responsible for their expression. The basal ganglia have been subdivided into 3 general territories: sensorimotor, associative and limbic. These subdivisions are based on anatomical connections and immunohistochemical staining patterns. This application will focus on the limbic territory. Prior studies have shown that micro-injections of the GABA antagonist, Bicuculline (Bic) into the limbic territory of the external segment of the Globus Pallidus (GPe) evoke abnormal behaviors including excessive grooming, nail biting, and communicative gestures. We will use transneuronal transport of rabies virus to identify the cortical areas that are interconnected with sites in GPe where Bic produces these behaviors. We propose two sets of experiments. First, we will behaviorally define specific sites in the limbic territory of GPe using Bic microinjections. Then, we will inject rabies virus in GPe and allow retrograde transneuronal transport to 2nd order neurons in the cerebral cortex. This approach will identify cortical neurons that provide input to the limbic territory in GPe. In a second set of experiments, we will again use Bic injections to define specific sites in the limbic territory of GPe. These sites with be marked by micro- lesions. Then, we will inject rabies virus into sites of interest in the cerebral cortex. These sites will be the sites that contained the highest density of labeled neurons in the first set of experiments. We will allow retrograde transneuronal transport to 3rd order neurons in GPe. We will compare the location of these GPe neurons to the marking lesions at GPe sites. This approach will identify cortical regions that are the targets of output from the limbic territory in GPe. Together these experiments should provide new insights into the cortical areas that are responsible for the non-motor symptoms of basal ganglia dysfunction. This information may result in new avenues for treatment of complex disorders like OCD and TS.