Basal Ganglia and Higher Cortical Function

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，还会导致与抑郁症、强迫症(OCD)和抽动症(TS)等神经精神障碍相关的行为症状。我们实验的总体目标是将与BG功能障碍相关的非运动症状与负责它们表达的皮质区域联系起来。基底节可分为感觉运动区、联合区和边缘区。这个应用程序将重点放在联合和边缘地区。以往的研究表明，将GABA拮抗剂荷包牡丹碱(Bicuculline，BIC)微量注射到苍白球(GPE)外段的联合和边缘区域，可可逆地引起异常行为。诱发的行为取决于GPE内注射的特定部位。BIC注射到联合区域会引起多动和注意力缺陷，而注射到GPE的边缘区域会引起过度的梳理、咬指甲和交流手势。我们认为，微量注射BIC产生的症状是由GPE异常信号的靶点--大脑皮层决定的。我们将使用狂犬病病毒的跨神经元传输来识别与GPE中具有行为特征的部位相互关联的皮质区域。我们提出了两组实验。在第一组实验中，我们将使用BIC微量注射从行为上确定GPE联合区域和边缘区域的位置。然后，我们将在GPE部位注射少量狂犬病病毒，并允许病毒逆行跨神经元运输，以标记大脑皮层的二级神经元。这种方法将识别为GPE中的联合区域和边缘区域提供输入的皮质神经元。在第二组实验中，我们将再次使用微量注射BIC来确定GPE联合区域和边缘区域的特定位置。这些部位将被标记为微小病变。然后，我们将狂犬病病毒注射到大脑皮层的特定区域，并允许逆行跨神经元运输来标记GPE中的三级神经元。我们将把这些GPE神经元的位置与GPE中的标记损伤进行比较。这种方法将确定GPE中作为联合和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抑郁症、强迫症和TS等复杂疾病开辟新的途径。公共卫生相关性拟议的研究将确定连接基底节和额叶皮质区域的互连矩阵。这些回路对于正常的认知和情感功能是必不可少的，而且它们似乎在各种神经精神障碍中出现功能障碍。因此，拟议的研究结果可能会为治疗抑郁症、强迫症和抽动症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 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 the behavioral symptoms associated with neuropsychiatric disorders like Depression, Obsessive-Compulsive Disorder (OCD) and Tourette Syndrome (TS). The overall goal of our experiments is to link the non-motor symptoms associated with BG dysfunction to the cortical areas that are responsible for their expression. The basal ganglia can be subdivided into 3 general territories: sensorimotor, associative and limbic. This application will focus on the associative and limbic territories. Prior studies have shown that microinjections of the GABA antagonist, Bicuculline (BIC) into the associative and limbic territories of the external segment of the globus pallidus (GPe) reversibly evoke abnormal behaviors. The behavior that is evoked depends on the specific site injected within GPe. BIC injections into the associative territory evoke hyperactivity and attentional deficits, whereas injections into the limbic territory of GPe evoke excessive grooming, nail biting, and communicative gestures. We propose that the symptoms produced by a microinjection of BIC are determined by the cortical areas that are the targets of the abnormal signals from GPe. We will use transneuronal transport of rabies virus to identify the cortical areas that are interconnected with behaviorally characterized sites in GPe. We propose two sets of experiments. In the first set of experiments, we will behaviorally define sites in the associative and limbic territories of GPe using BIC micro-injections. Then, we will inject a small amount of rabies virus at the GPe site and allow retrograde transneuronal transport of the virus to label 2nd order neurons in the cerebral cortex. This approach will identify the cortical neurons that provide input to the associative and limbic territories in GPe. In a second set of experiments, we will again use micro-injections of BIC to define specific sites in the associative and limbic territories of GPe. These sites will be marked with micro-lesions. Then, we will inject rabies virus into specific areas of the cerebral cortex and allow retrograde transneuronal transport to label 3rd order neurons in GPe. We will compare the location of these GPe neurons to the marking lesions in GPe. This approach will identify cortical areas that are the targets of output from the associative and limbic territories 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 lead to new avenues for treatment of complex disorders like Depression, OCD and TS. PUBLIC HEALTH RELEVANCE The proposed studies will define the matrix of interconnections that link the basal ganglia with cortical areas in the frontal lobe. These circuits are essential for normal cognitive and affective function, and they appear to be dysfunctional in a wide variety of neuropsychiatric disorders. Thus, the results of the proposed studies could lead to new avenues for treatment of complex disorders like Depression, Obsessive-Compulsive Disorder and Tourette Syndrome.