Using microstimulation to map prefrontal fear modules in the rat

使用微刺激绘制大鼠前额叶恐惧模块

• 批准号: 8076853
• 负责人: Gregory J Quirk
• 金额: $ 19.27万
• 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/8076853
• 关键词: Acute; Amygdaloid structure; Area; Axon; Basal Ganglia; Behavior; Behavioral; Clinical; Corpus striatum structure; Deep Brain Stimulation; Electrodes; Equilibrium; Extinction (Psychology); Fiber; Frequencies; Fright; Human; Instruction; Label; Lateral; Learning; Maps; Medial; Memory; Modeling; Neurons; Obsession; Obsessive-Compulsive Disorder; Output; Parvalbumins; Pattern; Primates; Process; Rattus; Rewards; Rodent; Rodent Model; Role; Site; Structure; Symptoms; Techniques; Testing; Therapeutic; Thinking; Time; Training; Translations; Travel; Ventral Striatum; avoidance behavior; capsule; conditioned fear; immunocytochemistry; learning extinction; microstimulation; novel; relating to nervous system; response

Obsessive compulsive disorder (OCD) is characterized by persistent intrusive thoughts (obsessions) and repetitive intentional behaviors (compulsions). The overall hypothesis of this center is that these symptoms are due, in part, to impaired extinction of fear, which disrupts the normal balance between fear avoidance and reward- seeking. These behaviors depend on medial prefrontal (mPFC)-orbitofrontal (OFC)-basal ganglia circuits, which are known to be dysfunctional in OCD. Deep brain stimulation (DBS) of sites in the ventral capsule/ventral striatum (VS/VS) region reduces OCD symptoms, but the mechanisms are unknown. The VS/VC contains fibers emanating from widespread areas of OFC and mPFC. Therefore, a thorough behavioral mapping of stimulation effects in mPFC, OFC, and VC/VS is needed to optimize electrode placement and understand the mechanisms of therapeutic action of DBS. Project 4 will carry out this mapping. In Aim 1, we will use acute microstimulation to map mPFC and OFC subregions in the expression and extinction of conditioned fear. In Aim 2, we will assess the effects of subchronic microstimulation of OFC and mPFC, and their output axons in the accumbens, in the transfer of fear extinction to instrumental avoidance, using a newly developed behavioral task in rats. By administering the stimulation at various times during training, we will be able to separately evaluate its effects on: 1) extinction learning and retention, 2) the transfer of Pavlovian extinction to instrumental avoidance, and 3) the persistence of avoidance behaviors despite extensive extinction (can microstimulation "cure" the rats by reducing preservative avoidance?) In Aim 3, we will correlate this behavioral mapping with a neural mapping, use immunocytochemical techniques to assess the activation patterns in OFC and mPFC induced by subchronic microstimulation of sites shown to be effective in our task. Mapping the behavioral and neural effects of DBS-like microstimulation in a rodent model will facilitate the translation of rodent circuit models to primates and humans, and could suggest new targets for DBS in OCD. In addition, it will increase our basic understanding of mPFC- OFC interactions, and the role of this network in regulating fear learning and expression. RELEVANCE (See instructions): While deep brain stimulation (DBS) has been shown to be effective in the treatment of OCD, little is known about its mechanisms. Mapping the effects of DBS-like microstimulation in a rodent model could suggest new targets for DBS in OCD. In addition, it will increase our basic understanding of mPFC-OFC interactions, and the role of this network in regulating fear learning and expression.

强迫症（OCD）的特征是持续的侵入性思想（痴迷）和 重复的故意行为（强迫）。该中心的总体假设是这些症状是 部分原因是恐惧的灭绝损害，这破坏了避免恐惧和奖励之间的正常平衡 - 寻求。这些行为取决于内侧前额叶（MPFC） - 轨道额（OFC） - 基质神经节电路 已知在强迫症中功能失调。腹胶囊/腹侧部位的深脑刺激（DB） 纹状体（VS/VS）区域可减少强迫症症状，但这些机制尚不清楚。 VS/VC包含纤维 从OFC和MPFC的广泛地区发出。因此，彻底对刺激的行为映射 需要对MPFC，OFC和VC/VS的影响来优化电极放置并了解 DBS的治疗作用。项目4将进行此映射。在AIM 1中，我们将使用急性微刺激 在条件恐惧的表达和灭绝中，MAP MPFC和OFC子区域。在AIM 2中，我们将评估 OFC和MPFC的亚慢性微刺激及其在伏伏氏症中的输出轴突的影响，在 恐惧灭绝向工具避免的转移，使用大鼠新发展的行为任务。经过 在训练期间的不同时间管理刺激，我们将能够分别评估其影响： 1）灭绝学习和保留率，2）将帕夫洛维亚灭绝转移到工具避免的情况下，3） 尽管存在广泛的灭绝，但避免行为的持久性（可以微刺激可以通过减少来“治愈”大鼠 防腐剂避免？）在AIM 3中，我们将将此行为映射与神经映射相关联，使用 免疫细胞化学技术，以评估SubChronic诱导的OFC和MPFC中的激活模式 对现象有效的站点的微刺激。绘制类似DBS的行为和神经效应 啮齿动物模型中的微刺激将有助于将啮齿动物电路模型转换为灵长类动物和人类， 并可能建议在强迫症中针对DBS的新目标。此外，这将增加我们对MPFC-的基本理解 OFC相互作用，以及该网络在调节恐惧学习和表达方面的作用。 相关性（请参阅说明）： 虽然已证明深脑刺激（DB）在OCD的治疗中有效，但鲜为人知 关于它的机制。在啮齿动物模型中绘制DBS样微刺激的效果可能建议 OCD中DBS的新目标。此外，它将增加我们对MPFC-OFC相互作用的基本理解， 以及该网络在调节恐惧学习和表达方面的作用。