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致残的僵硬行为。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，影响人们的整个生命周期。由于我们对潜在的细胞和电路机制缺乏了解，因此对强迫症的有效治疗方法的开发受到了阻碍。为了满足这一需求，我们已经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当地的纹状体电路。我们建议：（1）检验我们的假设，即纹状体1型代谢型谷氨酸受体（mGluRs）的过度活性驱动小鼠的强迫样行为，（2）建立在我们最近通过确定mGluR 1信号传导是否也在具有OCD样行为的小鼠中失调来定义mGluR 5失调的作用的进展基础上，（3）评估异常纹状体组1 mGluR信号传导对具有OCD样行为的小鼠的纹状体输出的综合影响，以及（4）确定mGluR-纹状体输出的依赖性重构是与强迫行为的动物模型相关的常见机制。总之，这些研究有可能通过提供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，从而实现范式转变。这样的临床前结果将新的注意力转向这种高度可药用的受体类别，并阐明特定的细胞和电路机制，以促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.