In vivo neurocircuitry of DBS response in rodents

啮齿类动物 DBS 反应的体内神经回路

• 批准号: 8076854
• 负责人: ANTHONY A GRACE
• 金额: $ 21.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076854
• 关键词: Affect; Anesthesia procedures; Animals; Area; Behavior; Behavioral; Brain; Chronic; Clinical; Collaborations; Custom; Data; Elements; Emotional; Equilibrium; Extinction (Psychology); FOS gene; Fiber; Frequencies; Functional disorder; Hour; Human; Hyperactive behavior; Image; Implant; In Vitro; Instruction; Interneurons; Label; Lateral; Lesion; Measurement; Nature; Neurons; Obsessive-Compulsive Disorder; Patients; Phase; Play; Primates; Rattus; Rodent; Role; Secondary to; Site; Stimulus; Synaptic plasticity; System; Testing; Therapeutic; Therapeutic Effect; Time; Work; analog; awake; base; comparative; design; hippocampal pyramidal neuron; immunocytochemistry; in vivo; prevent; research study; response; time interval

Imaging studies suggest that obsessive-compulsive disorder (OCD) may be due to overactivity within the lateral orbitofrontal cortex (LO); an area known to be important in stimulus valuation. Secondly, the vmPFC has been suggested to play a role based on its function in extinction. We propose that OCD is due to a dysfunction of hyperactivity within the LO, causing the patient to over-value a stimulus that is no longer behaviorally salient, and hypoactivity within the vmPFC, interfering with normal extinction of nonsalient stimuli. High-frequency stimulation (HFS) of the brain, is proposed to act therapeutically by restoring normal function to these circuits. This project uses in vivo recordings of LO and vmPFC activity and how these circuits respond to HFS of the NAc, which is the rodent analog of the stimulation site found to be effective in treating OCD in humans. Stimuli will be presented acutely, subchronically (90 min-8 hours), and chronically using implanted custom-designed stimulators (2 weeks) to evaluate the changes that occur during the course of stimulation. These changes will be evaluated in terms of rhythmic activity, neuronal firing, and synaptic plasticity changes that occur over these time intervals. A unique component to this proposal is that stimulation and most measurements will be performed in the awake animal to circumvent anesthesia issues. This study will be done along three specific aims: 1) Examine the effects of subchronic HFS stimulation of the NAc site on mPFC, LO and NAc spontaneous and evoked fields, along with c-fos to evaluate which neuron types are affected. 2) Examine chronic HFS effects on vmPFC, LO and NAc activity states and the time course of the changes. During the last day of stimulation, animals will be anesthetized and recordings of neurons identified by juxtacellular labeling and immunocytochemistry to assess the cellular nature of the changes observed. 3) Examine the effects of chronic HFS on mPFC-LO interactions to evaluate whether the changes observed in vmPFC are dependent on the LO, and vice-versa. We propose that HFS will decrease LO activity to decrease the emotional salience of the stimulus, while activating the mPFC to facilitate extinction; both of which may be required for a therapeutic response. Such information will provide essential data with respect to HFS effects at a systems level, as well as how network interactions can modulate regionally-selective alterations at the cellular level. Furthermore, this project will provide essential information to evaluate the imaging and clinical findings, the alterations in activity that will be tested in behavioral experiments, and the neuronal types activated for comparison with the in vitro cellular analyses. RELEVANCE (See instructions): This study will provide information regarding the modulation and interaction of cortical circuits proposed to have a role in OCD, as well as mechanisms by which rhythmic activity is modulated within these circuits. In addition, it will provide a cellular basis for the therapeutic effects of HFS used in the treatment of OCD, and help to refine the stimulation sites and parameters to most effectively induce the desired changes.

影像学研究表明，强迫症（OCD）可能是由于过度活跃，在 外侧眶额皮质（LO）;已知在刺激评价中重要的区域。其次，vmPFC 根据其在灭绝中的作用，有人认为它发挥了作用。我们认为强迫症是由于 LO内的过度活跃功能障碍，导致患者过度重视不再是刺激的刺激。 行为上的显著性，以及vmPFC内的活动减退，干扰了非显著性的正常消退 刺激。高频刺激（HFS）的大脑，提出了治疗作用，恢复正常 这些电路的功能。该项目使用LO和vmPFC活动的体内记录，以及这些活动是如何发生的。 回路对NAc的HFS作出反应，NAc是被发现有效的刺激部位的啮齿动物模拟物， 治疗人类的强迫症刺激将以急性、亚慢性（90分钟-8小时）和慢性方式呈现 使用植入的定制设计的刺激器（2周）来评估在 刺激的过程。这些变化将根据节律活动、神经元放电和 突触可塑性的变化发生在这些时间间隔。这项建议的一个独特组成部分是， 刺激和大多数测量将在清醒的动物中进行以避免麻醉问题。 本研究将沿着沿着三个具体目标进行：1）检查亚慢性HFS刺激对神经细胞的影响。 NAc在mPFC、LO和NAc自发和诱发野上的位置，沿着c-fos，以评估 神经元类型受到影响。2)检查慢性HFS对vmPFC、LO和NAc活动状态的影响， 变化的时间过程。在刺激的最后一天，将对动物进行麻醉，并记录 神经元鉴定的细胞标记和免疫细胞化学，以评估细胞的性质， 观察到的变化。3)检查慢性HFS对mPFC-LO相互作用的影响，以评估 在vmPFC中观察到的变化取决于LO，反之亦然。我们建议HFS将减少 LO活动降低刺激的情绪显著性，同时激活mPFC以促进 消退;这两者都可能是治疗反应所需的。这些信息将提供重要的 关于系统级HFS效应的数据，以及网络交互如何调节 在细胞水平上的区域选择性改变。此外，该项目将提供必要的 评估成像和临床结果的信息，将在 行为实验，以及与体外细胞分析比较的激活的神经元类型。 相关性（参见说明）： 这项研究将提供有关皮质回路的调制和相互作用的信息， 在强迫症中起作用，以及在这些回路中调节节律活动的机制。在 此外，它将为HFS用于治疗强迫症的治疗效果提供细胞基础， 有助于细化刺激部位和参数，以最有效地诱导期望的变化。