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.

影像研究表明，强迫症(OCD)可能是由于体内活动过度所致 外侧眶前叶皮质(LO)；已知在刺激评估中重要的区域。其次，vmPFC 已经被建议根据其在灭绝中的功能来发挥作用。我们认为强迫症是由于 LO内的多动功能障碍，导致患者高估不再存在的刺激 行为显著，vmPFC内活动不足，干扰不显著的正常消退 刺激物。脑的高频刺激(HFS)被认为是通过恢复正常而起到治疗作用的 对这些电路起作用。该项目使用LO和vmPFC活动的活体记录，以及这些 电路对NAC的HFS做出反应，NAC是被发现有效的刺激部位的啮齿动物类似物 治疗人类的强迫症。刺激将以急性、亚时态(90分钟-8小时)和慢性的方式呈现 使用植入的定制设计的刺激器(2周)评估在治疗期间发生的变化 刺激过程。这些变化将通过节律活动、神经元放电和 在这些时间间隔内发生的突触可塑性变化。这项提议的一个独特之处在于 刺激和大多数测量将在清醒的动物身上进行，以避免麻醉问题。 这项研究将沿着三个特定的目标进行：1)检测亚慢性HFS刺激的影响 NAC定位于mPFC、LO和NAC自发野和诱发野，并结合c-fos评价 神经元类型受到影响。2)研究慢性HFS对vmPFC、LO和NAC活动状态的影响以及 变化的时间进程。在刺激的最后一天，动物将被麻醉并记录 用细胞旁标记和免疫细胞化学鉴定神经元以评估细胞性质 观察到了变化。3)检测慢性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活动能降低情绪刺激的显着性，同时激活mPFC以促进 消退；两者都可能是治疗反应所必需的。这些信息将提供重要的 与系统级别的HFS效应有关的数据，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 评估影像和临床表现的信息，将在 行为学实验，并将激活的神经元类型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大脑皮层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……里面 此外，它还将为HFS用于治疗强迫症的疗效提供细胞基础，以及 帮助改进刺激部位和参数，以最有效地诱导所需的变化。