NMDAR Modulation As A Therapeutic Target and Probe of Neural Dysfunction in OCD

 描述(申请人提供)：强迫症(OCD)的特征是缺乏对重复思想(强迫症)和行为(强迫症)的认知(努力)控制，并与额叶纹状体回路功能障碍有关。用5-羟色胺再摄取抑制剂(SRIs)治疗强迫症会导致较长的滞后时间(2-3个月)，直到临床受益，这通常只是部分有效。确定有效、快速的治疗方法将有助于预防强迫症的发病率。我们发现，在没有SRI的情况下，单次静脉输注N-甲基-D-天冬氨酸(NMDA)受体拮抗剂氯胺酮可以迅速降低强迫症的严重程度。动物研究发现，额纹状体活动调节是强迫症样重复行为的关键驱动因素，谷氨酸突触编码突触后支架蛋白的基因敲除导致额纹状体活动改变、强迫症样行为和NMDAR亚单位表达增加。综上所述，这些研究支持NMDA受体作为强迫症相关行为的一个有前途的新靶点。这款R01将在分子、电路和网络同步的水平上测试氯胺酮对成人强迫症治疗作用的急性机制。我们使用一种新的方法来同时研究NMDA受体拮抗引起的空间和时间的脑功能变化。目前的理论认为，强迫症患者基线时观察到的额叶-纹状体过度活动是由于抑制性和兴奋性神经网络功能障碍所致。与这些理论一致，我们发现与健康对照组相比，强迫症患者内侧前额叶皮质(MPFC)的抑制性神经递质伽马氨基丁酸(GABA)存在缺陷。我们还发现，强迫症受试者单剂量静注氯胺酮后1小时，MPFC、GABA显著增加。在健康对照组中，前额叶GABA的增加与伽马振荡的诱导有关，伽马振荡是该区域局部抑制回路的潜在生物标记物。基于我们的发现，我们提出了一个可测试的工作模型，说明氯胺酮如何降低强迫症的严重程度，这些严重程度与GABA、额叶-纹状体回路的功能连接和网络同步有关。该R01的总体目标是确定NMDA受体拮抗如何修改疾病特异性病理以缓解重复的思想和行为。拟议的项目使用跨多个分析单元(分子、电路和网络同步)的多模式成像方法，以便为快速作用疗法(以NMDAR拮抗为第一个新目标)改变精神治疗开辟一条新的途径。

 DESCRIPTION (provided by applicant): Obsessive-Compulsive Disorder (OCD) is characterized by a lack of cognitive (effortful) control over repetitive thoughts (obsessions) and behaviors (compulsions) and is associated with dysfunction in fronto- striatal circuits. Treatment of OCD with serotonin reuptake inhibitors (SRIs) results in a long lag time (2-3 months) before clinical benefit that is typically only partially effective. Identification of effective, fast-actig treatments will help prevent OCD morbidity. We found that a single IV infusion of an N-methyl-D-Aspartate (NMDA) receptor antagonist, ketamine, can rapidly reduce OCD severity in the absence of an SRI. Animal studies find fronto-striatal activity modulation is a critical driver of OCD-like repetitive behaviors, with knockout of a gene encoding a postsynaptic scaffolding protein at glutamate synapses leading to altered fronto-striatal activity, OCD-like behavior, and elevated expression of NMDAR subunits. Taken together, these studies support the NMDA receptor as a promising new target for OCD-relevant behaviors. This R01 will test the acute mechanism of ketamine's therapeutic action in adults with OCD at the level of molecules, circuits, and network synchrony. We use a novel approach to simultaneously study both spatial and temporal functional brain changes caused by NMDA receptor antagonism. Current theories posit that the fronto-striatal hyperactivity observed in OCD at baseline is due to dysfunction in inhibitory and excitatory neural networks. Consistent with these theories, we find deficits in the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the medial prefrontal cortex (MPFC) in OCD compared to healthy controls. We also discovered that OCD subjects given a single dose of IV ketamine show a significant increase of MPFC GABA 1 hour post-infusion. In healthy controls, increases in prefrontal GABA are correlated with the induction of gamma oscillations, a potential biomarker for local inhibitory circuits within this region. Based on our findings, we propose a testable working model for how the ketamine may decrease OCD severity that links GABA, functional connectivity in frontal- striatal circuits, and network synchrony. The overall goal of this R01 is to determine how NMDA receptor antagonism modifies disease-specific pathology to relieve repetitive thoughts and behaviors. The proposed projects use a multimodal imaging approach across multiple units of analysis (molecules, circuits, and network synchrony) in order to open a new avenue for rapid acting therapeutics (with NMDAR antagonism as a first new target) to transform psychiatric treatments.