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

 描述（由申请人提供）：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-纹状体回路功能障碍相关。用5-羟色胺再摄取抑制剂（SRI）治疗强迫症导致在临床获益之前的较长滞后时间（2-3个月），其通常仅部分有效。确定有效、快速的治疗方法将有助于预防强迫症的发病。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OCD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，敲除谷氨酸突触处编码突触后支架蛋白的基因会导致额-纹状体活动改变、强迫症样行为和NMDAR亚基表达升高。总之，这些研究支持NMDA受体作为一个有前途的新的目标，强迫症相关的行为。本R 01将在分子、回路和网络同步水平上测试氯胺酮对成人强迫症的治疗作用的急性机制。我们使用一种新的方法，同时研究空间和时间的NMDA受体拮抗剂引起的脑功能的变化。目前的理论认为，在强迫症中观察到的额-纹状体过度活跃是由于抑制性和兴奋性神经网络功能障碍。与这些理论相一致，我们发现与健康对照组相比，强迫症患者内侧前额叶皮层（MPFC）中的抑制性神经递质γ-氨基丁酸（GABA）存在缺陷。我们还发现，给予单剂量IV氯胺酮的OCD受试者在输注后1小时显示出MPFC GABA的显著增加。在健康对照组中，前额叶GABA的增加与γ振荡的诱导相关，γ振荡是该区域内局部抑制回路的潜在生物标志物。基于我们的发现，我们提出了一个可测试的工作模型，用于研究氯胺酮如何降低OCD的严重程度，该模型将GABA、额叶-纹状体回路中的功能连接和网络同步联系起来。R 01的总体目标是确定NMDA受体拮抗作用如何改变疾病特异性病理学，以减轻重复的想法和行为。拟议的项目使用跨多个分析单元（分子，电路和网络同步）的多模态成像方法，以便为快速作用疗法（以NMDAR拮抗作用为第一个新靶点）开辟新途径，以改变精神病治疗。

 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.