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）可能是由于大脑内部过度活动造成的。 外侧眶额皮层 (LO)；已知在刺激评估中很重要的领域。其次，vmPFC 根据其在灭绝中的功能，有人建议发挥作用。我们认为强迫症是由于 LO 内过度活跃的功能障碍，导致患者高估不再有效的刺激 行为显着性和 vmPFC 内的低活性，干扰非显着性的正常消退 刺激。大脑的高频刺激（HFS）被提议通过恢复正常来起到治疗作用 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如何 电路对 NAc 的 HFS 做出反应，NAc 是刺激部位的啮齿动物类似物，被发现在以下方面有效： 治疗人类强迫症。刺激将以急性、亚慢性（90 分钟至 8 小时）和慢性的方式呈现 使用植入的定制刺激器（2周）来评估在治疗过程中发生的变化 刺激过程。这些变化将根据节律活动、神经元放电和 在这些时间间隔内发生的突触可塑性变化。该提案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。 这项研究将围绕三个具体目标进行：1）检查亚慢性 HFS 刺激的影响 mPFC、LO 和 NAc 自发场和诱发场上的 NAc 位点，以及 c-fos 来评估哪些 神经元类型受到影响。 2) 检查慢性 HFS 对 vmPFC、LO 和 NAc 活动状态的影响以及 变化的时间过程。在刺激的最后一天，动物将被麻醉并记录 通过细胞旁标记和免疫细胞化学鉴定神经元，以评估神经元的细胞性质 观察到的变化。 3) 检查慢性 HFS 对 mPFC-LO 相互作用的影响，以评估是否 vmPFC 中观察到的变化取决于 LO，反之亦然。我们建议HFS会减少 LO 活动可降低刺激的情绪显着性，同时激活 mPFC 以促进 灭绝；治疗反应可能需要这两者。此类信息将提供必要的 有关系统级别 HFS 效应的数据，以及网络交互如何调节 细胞水平上的区域选择性改变。此外，该项目将提供必要的 评估影像和临床结果的信息，以及将要测试的活动变化 行为实验，以及激活的神经元类型以与体外细胞分析进行比较。 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 在强迫症中发挥作用，以及在这些回路中调节节律活动的机制。在 此外，它将为用于治疗强迫症的 HFS 的治疗效果提供细胞基础，以及 有助于细化刺激部位和参数，以最有效地引起所需的变化。