Role of basal ganglia circuit imbalance in the expression of OCD-like behaviors

基底神经节回路失衡在强迫症样行为表达中的作用

基本信息

批准号：
7900843
负责人：
JONATHAN T TING
金额：
$ 5.22万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2011-09-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Obsessive compulsive disorder (OCD) and related neurological disorders are estimated to afflict roughly 2% of the world population. The causes for these disorders are not well understood, and as such, effective intervention strategies are lacking. Although one promising hypothesis states that activity imbalance between the direct versus indirect striatal projection pathways of the basal ganglia underlies OCD-like behaviors, there have been no direct tests of this hypothesis to date. I will investigate the role of activity imbalance in the direct versus indirect pathways of the basal ganglia in the expression of OCD-like behaviors in mice through two complementary specific aims. Specific Aim 1 will make use of the recently described SAPAP3 knockout mouse model of OCD-like behavior, which was developed in our lab (Welch et al, 2007 Nature). Although previous work demonstrated general cortico-striatal glutamatergic synaptic defects in mixed populations of striatal medium spiny neurons (MSNs), our working hypothesis is that divergent defects with potentially salient physiological impacts may occur in direct versus indirect pathway-projecting MSNs. I will perform whole-cell electrophysiology on direct and indirect pathway-projecting MSNs to test for pathway specific defects that could not previously be resolved from mixed population recordings. In Specific Aim 2 I will generate novel transgenic mouse lines to directly silence neuronal activity in the direct and/or indirect pathways in vivo. This approach will allow inducible and reversible silencing of the specific pathway of interest in awake behaving mice, and thus will provide the most direct test to date of the contribution of pathway specific activity imbalance to quantifiable OCD-like behaviors. Analysis of these animals will be carried out by combined behavioral and electrophysiological assessment. By altering the balance of activity in the direct versus indirect pathways through selective pathway silencing I expect to elucidate general mechanisms of basal ganglia circuit dysfunction that are central to the expression of OCD-like behaviors. This work promises to significantly advance our understanding of the etiology of clinically relevant forms of OCD, and further to identify novel pharmacological targets for treatment of a wide range of related neurological disorders in humans.

描述（由申请人提供）：强迫症（OCD）和相关神经系统疾病估计约占世界人口的2％。这些疾病的原因尚不清楚，因此缺乏有效的干预策略。尽管一个有希望的假设指出，基底神经节的直接与间接纹状体投影途径之间的活动不平衡是OCD样行为的基础，但迄今为止尚无该假设的直接检验。我将通过两个互补的特定目的来研究活性不平衡在基底神经节在小鼠中表达OCD样行为中直接与间接途径中的作用。具体目标1将利用最近描述的SAPAP3敲除小鼠类似OCD样行为的模型，该模型是在我们的实验室中开发的（Welch等，2007年）。尽管先前的工作表明，纹状体培养基神经元混合种群（MSN）中的一般皮质 - 纹状体谷氨酸能突触缺陷（MSN），我们的工作假设是，在直接与间接途径探测MSN的直接相对于间接途径途径中可能会出现具有潜在明显生理影响的不同缺陷。我将在直接和间接途径的MSN上执行全细胞电生理学，以测试以前无法从混合种群记录中解决的途径特定缺陷。在特定的目标2中，我将生成新型的转基因小鼠系，以直接在体内直接和/或间接途径中直接静音神经元活性。这种方法将允许诱导和可逆的沉默对醒着的行为小鼠的特定感兴趣途径，因此将提供最直接的测试，迄今为止，途径特定活动不平衡对可量化的OCD类似行为的贡献。这些动物的分析将通过行为和电生理评估组合进行。通过选择性途径沉默，通过改变直接途径和间接途径的活性平衡，我希望阐明基底神经节电路功能障碍的一般机制，这对于OCD样行为表达至关重要。这项工作有望大大提高我们对OCD临床相关形式的病因的理解，并进一步确定新型的药理学靶标，以治疗人类广泛的相关神经系统疾病。