Investigating the interplay between ventral tegmental area dopamine, medial orbitofrontal cortex, and ventromedial striatum in compulsive-like behavior

摘要 强迫症(OCD)是全球十大致残原因之一。强迫症的现有治疗方法 都是不完整的，这强调了需要更彻底地了解强迫症的神经元基础。 病理学。大量文献提示内侧眶前叶皮质(MOFC)和腹内侧纹状体 强迫症患者(VMS)过度活跃，OCD与VMS中多巴胺的增加有关。小才是 然而，我们知道这些网络中的神经元是如何沟通或相互作用来产生强迫症症状的。 这项建议的首要目标是阐明mOFC和VTA多巴胺如何投射到VMS 有助于强迫症行为的发展。中心假设是1)VTA多巴胺 皮质纹状体回路的调节和2)皮质纹状体网络的过度同步性和连贯性 有助于这种表型的诱导。强迫症样行为将通过重复的光遗传来模拟 刺激EMX-cre小鼠VMS中的mOFC终末，导致进行性的，神经可塑性的诱导 重复的梳理。电生理活动将在mOFC和VMS中同时记录 强迫症样表型的诱导，以确定这些网络如何作为这种病理性的沟通方式 建立行为(目标1)。VTA激发模式的变化将通过记录 表型诱导过程中的电生理活动，以及光遗传光标记将被用于 识别多巴胺能神经元(目标2)。最后，抑制性设计者受体被Designer独家激活 药物(DREADD)将被用来确定VTA多巴胺是否是诱导强迫症样症所必需的 打扮(目标3)。这些实验将提供有关区域间网络相互作用的新信息 潜在的强迫症相关行为表型。揭示这些互动的动态，以及它们的 随着强迫行为的发展，进化将揭示与强迫症相关的神经病理学的有价值的信息 这将有力地为基于网络的强迫症行为和强迫症病理理论提供信息。这 提案通过包含多种方法提供广泛的培训机会，这些方法包括 给申请者的小说，包括光遗传学，化学遗传学，自然行为分析，转基因 小鼠疾病模型和多区域神经元操作。因此，这一综合研究和培训 计划将提供对未来职业发展(K)奖励和最终独立的关键技能 调查员位置。

ABSTRACT Obsessive-compulsive disorder (OCD) is a top ten cause of disability worldwide. Existing treatments for OCD are incomplete, which underscores the need for a more thorough understanding of the neuronal basis of OCD pathology. An extensive literature suggests the medial orbitofrontal cortex (mOFC) and ventromedial striatum (VMS) are hyperactive in OCD patients, and that OCD is associated with increased dopamine in VMS. Little is known, however, about how neurons in these networks communicate or interact to produce OCD symptoms. The overarching goal of this proposal is to elucidate how mOFC and VTA dopamine projections to VMS contribute to development of compulsive-like behaviors. The central hypotheses are 1) VTA dopamine regulation of corticostriatal circuitry and 2) excessive synchrony and coherence in corticostriatal networks contribute to induction of this phenotype. Compulsive-like behaviors will be modeled via repeated optogenetic stimulation of mOFC terminals in VMS of EMX-cre mice, which causes a progressive, neuroplastic induction of repetitive grooming. Electrophysiological activity will be recorded simultaneously in mOFC and VMS during induction of the compulsive-like phenotype to determine how these networks communicate as this pathological behavior is established (Aim 1). Changes in VTA firing patterns will be assessed by recording electrophysiological activity during induction of the phenotype, and optogenetic phototagging will be used to identify dopaminergic neurons (Aim 2). Finally, inhibitory designer receptors exclusively activated by designer drugs (DREADDs) will be used to determine if VTA dopamine is necessary for induction of compulsive-like grooming (Aim 3). These experiments will provide novel information on the interregional network interactions underlying OCD-related behavioral phenotypes. Uncovering the dynamics of these interactions, and their evolution as compulsive behaviors develop, will reveal valuable information on neuropathology related to OCD that will strongly inform network based theories of compulsive-like behaviors and OCD pathologies. This proposal provides extensive training opportunities through the inclusion of numerous methodologies that are novel to the applicant, including optogenetics, chemogenetics, analysis of naturalistic behaviors, transgenic mouse models of disease, and multi-region neuronal manipulations. Thus, this integrated research and training plan will provide skills that are critical for a future career development (K) award and an eventual independent investigator position.