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

研究强迫样行为中腹侧被盖区多巴胺、内侧眶额皮质和腹内侧纹状体之间的相互作用

基本信息

  • 批准号:
    9393053
  • 负责人:
  • 金额:
    $ 5.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-01 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

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.
摘要 强迫症(OCD)是世界范围内十大残疾原因之一。强迫症的现有治疗方法 是不完整的,这强调了需要更彻底地了解强迫症的神经基础 病理大量文献表明内侧眶额皮质(mOFC)和腹内侧纹状体 (VMS)在强迫症患者中是过度活跃的,强迫症与VMS中多巴胺的增加有关。之甚少 然而,关于这些网络中的神经元如何交流或相互作用以产生强迫症症状,我们还不清楚。 这项建议的首要目标是阐明mOFC和VTA多巴胺投射到VMS的机制。 有助于强迫性行为的发展。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 有助于诱导这种表型。将通过重复的光遗传学来模拟nae sive样行为, 刺激EMX-cre小鼠VMS中的mOFC终末,这会导致渐进性的神经可塑性诱导, 重复梳理毛发电生理活动将同时记录在mOFC和VMS中, 诱导强迫样表型,以确定这些网络如何沟通,因为这种病理 建立行为(目标1)。将通过记录VTA放电模式的变化来评估 表型诱导期间的电生理活性,并且光遗传学光标记将用于 鉴定多巴胺能神经元(目的2)。最后,抑制性设计者受体仅由设计者激活, 药物(DREADDs)将被用来确定是否VTA多巴胺是必要的诱导强迫样 梳理(目标3)。这些实验将为区域间网络互动提供新的信息 潜在的强迫症相关行为表型揭示这些相互作用的动态,以及它们的 随着强迫行为的发展而演变,将揭示与强迫症相关的神经病理学的宝贵信息 这将有力地为基于网络的强迫性行为和强迫症病理理论提供信息。这 建议通过纳入许多方法提供了广泛的培训机会, 对申请人来说是新颖的,包括光遗传学、化学遗传学、自然行为分析、转基因 疾病的小鼠模型和多区域神经元操作。因此,这种综合研究和培训 该计划将提供对未来职业发展(K)奖励和最终独立的技能 调查员职位。

项目成果

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