Cortico-striatal neurotransmission and compulsive motor behaviors

描述(由申请人提供)：强迫性运动行为反映了正常适应性行为反应的丧失，并导致严重程度从有害到残疾的僵硬行为。强迫症(OCD)是这类行为障碍的典型形式，但适应不良的强迫症出现在不同的背景下，影响着人们的一生。由于我们缺乏对潜在的细胞和电路机制的了解，有效治疗强迫症的方法的发展一直受到阻碍。为了满足这一需求，我们组装了一套独特的遗传试剂，并开发了一种新的方法来检查局部纹状体回路。我们建议：(1)测试我们的假设，即纹状体第1组代谢性谷氨酸受体(MGluRs)的过度活动会驱动小鼠的强迫行为；(2)以我们最近的进展为基础，通过确定mGluR5信号在强迫症样行为小鼠中是否也受到失调，来定义mGluR5失调的角色；(3)评估纹状体1组mGluR异常信号对强迫症样行为小鼠纹状体输出的综合影响；以及(4)确定依赖mGluR的纹状体输出重构是否是与强迫症行为动物模型相关的常见机制。总而言之，这些研究提供了第一个直接的实验证据，支持纹状体第一组mGluRs在导致强迫运动行为中的作用，从而有可能改变范式。这些临床前的结果将重新引导人们对这类高度可药物的受体的关注，并阐明特定的细胞和电路机制，以推进人类相关疾病的治疗。

DESCRIPTION (provided by applicant): Compulsive motor behaviors reflect a loss of normal adaptive behavioral responsiveness and result in rigid behaviors that range in severity from detrimental to disabling. Obsessive compulsive disorder (OCD) is the prototypical form of such behavioral disorders, but maladaptive compulsions emerge in diverse contexts affecting people across the lifespan. Development of effective therapeutics for compulsivity has been hampered by our lack of understanding of the underlying cellular and circuit mechanisms. In order to address this need, we have assembled a unique set of genetic reagents and developed a novel approach to examine the local striatal circuit. We propose to: (1) test our hypothesis that overactivity of striatal group 1 metabotropic glutamate receptors (mGluRs) drives compulsive-like behaviors in mice, (2) build upon our recent progress of defining a role for mGluR5 dysregulation by determining whether mGluR1 signaling is also dysregulated in mice with OCD-like behaviors, (3) evaluate the integrated effects of abnormal striatal group 1 mGluR signaling on striatal output in mice with OCD-like behaviors and (4) determine whether mGluR-dependent reconfiguration of striatal output is a common mechanism associated with animal models for compulsive behaviors. Together these studies have the potential to be paradigm-shifting by providing the first direct experimental evidence to support a role for striatal group 1 mGluRs in causing compulsive motor behaviors. Such preclinical results will newly direct attention to this highly druggable class of receptors as well as illuminate specific cellular and circuit mechanisms to advance the treatment of related disorders in humans.