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，并导致从有害到致残的严重程度的僵硬行为。强迫症（OCD）是这种行为障碍的典型形式，但适应不良的强迫症出现在不同的环境中，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理解，强迫症的有效治疗方法的发展受到了阻碍。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)验证纹状体1组代谢性谷氨酸受体（mGluRs）过度活跃驱动小鼠强迫样行为的假设；(2)基于我们最近的研究进展，通过确定mGluR1信号是否也在强迫症样行为小鼠中失调，来确定mGluR5失调的作用；(3)评估异常纹状体1组mGluR信号对强迫症样行为小鼠纹状体输出的综合影响；(4)确定依赖于mGluR的纹状体输出重构是否是与强迫行为动物模型相关的共同机制。这些研究提供了第一个直接的实验证据来支持纹状体1组mGluRs在引起强迫性运动行为中的作用，从而有可能改变范式。这样的临床前研究结果将重新引导人们关注这类高度可药物化的受体，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.