Using microstimulation to map prefrontal fear modules in the rat

强迫症（OCD）的特征是持续的侵入性想法（强迫症）， 强迫行为（compulsory）。该中心的总体假设是，这些症状是 部分原因是恐惧消退受损，这破坏了恐惧回避和奖励之间的正常平衡， 寻找这些行为依赖于内侧前额叶（mPFC）-眶额（OFC）-基底神经节回路， 在强迫症中是功能失调的腹侧囊/腹侧部位的脑深部电刺激（DBS） 纹状体（VS/VS）区可减轻强迫症症状，但其机制尚不清楚。VS/VC含有纤维 来自眶额皮层和中前额叶皮层的广泛区域。因此，彻底的刺激行为映射 mPFC、OFC和VC/VS中的效应，以优化电极放置并了解 DBS的治疗作用。项目4将进行这一测绘。在目标1中，我们将使用急性微刺激， 映射mPFC和OFC子区域在条件性恐惧的表达和消退中的作用。在目标2中，我们将评估 亚慢性微刺激OFC和mPFC及其输出轴突在延髓中的作用， 转移的恐惧灭绝工具回避，使用新开发的大鼠行为任务。通过 在训练期间的不同时间给予刺激，我们将能够单独评估其对以下方面的影响： 1)灭绝学习和保留，2）巴甫洛夫灭绝工具回避的转移，和3） 回避行为的持久性，尽管广泛灭绝（微刺激可以“治愈”大鼠， 防腐剂回避？）在目标3中，我们将把这种行为映射与神经映射联系起来，使用 免疫细胞化学技术来评估亚慢性氧化应激诱导的OFC和mPFC的激活模式。 在我们的任务中显示有效的部位的微刺激。绘制类DBS的行为和神经效应 啮齿动物模型中的微刺激将促进啮齿动物回路模型向灵长类动物和人类的转化， 并可能为强迫症患者的DBS提供新的靶点。此外，它将增加我们对mPFC的基本了解- OFC的相互作用，以及这个网络在调节恐惧学习和表达中的作用。 相关性（参见说明）： 虽然脑深部电刺激（DBS）已被证明是有效的治疗强迫症， 关于它的机制。在啮齿动物模型中绘制DBS样微刺激的影响可能表明 DBS治疗强迫症的新目标此外，它将增加我们对mPFC-OFC相互作用的基本理解， 以及这个网络在调节恐惧学习和表达中的作用。

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.