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.

成像研究表明，强迫症（OCD）可能是由于在 外侧眶额皮质（LO）;已知在刺激评估中很重要的区域。其次，VMPFC 有人建议根据其灭绝功能扮演角色。我们建议强迫症是由于 LO内多动症的功能障碍，导致患者过度值不再是不再是的刺激 在行为上显着，VMPFC内的不良性，会干扰非正常的灭绝 刺激。大脑的高频刺激（HFS）提议通过恢复正常 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 电路对NAC的HF响应，这是刺激位点的啮齿动物类似物，发现有效 在人类中治疗强迫症。刺激将急性，下次（90分钟至8小时），并且长期出现 使用植入的自定义设计的刺激器（2周）来评估 刺激过程。这些变化将根据有节奏活动，神经元的射击和 在这些时间间隔内发生的突触可塑性变化。该提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，以绕过麻醉问题。 这项研究将按照三个具体目的进行：1）检查亚慢性HFS刺激的影响 MPFC，LO和NAC自发和诱发的田地上的NAC站点以及C-Fos评估哪个 神经元类型受到影响。 2）检查慢性HFS对VMPFC，LO和NAC活性状态以及 变化的时间课程。在刺激的最后一天，动物将被麻醉，并记录 通过并置标记和免疫细胞化学来鉴定的神经元，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，以评估是否是否 在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活动以减少刺激的情绪显着性，同时激活MPFC以促进 灭绝；这两者都是治疗反应所必需的。这样的信息将提供必不可少的 在系统级别上有关HFS效应的数据，以及网络交互如何调制 区域选择性改变在细胞水平上。此外，该项目将提供必不可少的 信息以评估成像和临床发现，将在 行为实验和激活的神经元类型，以与体外细胞分析进行比较。 相关性（请参阅说明）： 这项研究将提供有关提出的皮质电路调节和相互作用的信息 在OCD中起作用，以及在这些电路中调节节奏活动的机制。在 此外，它将为用于治疗强迫症的HF的治疗作用提供细胞基础，并为OCD治疗和 帮助完善刺激位点和参数，以最有效地诱导所需的变化。