Dissecting the role of medial versus lateral orbitofrontal circuit activity in perseverative behavior

项目总结/摘要：持续性行为是突出的，致残的，通常是治疗- 包括强迫症（OCD）在内的几种神经精神障碍的顽固症状。 持续行为指的是重复或持续的反应，不再导致奖励或奖励。 预期的结果。人类神经影像学数据与眶额-纹状体内异常活动相关 强迫症患者的持续行为。虽然早期的人类神经成像研究发现 整个眶额皮质（OFC）的过度激活，最近的研究表明， 外侧OFC（lOFC）和内侧OFC活动减退（mOFC）伴强迫症症状。此外，临床前 在啮齿动物中的研究表明，激活mOFC-纹状体投射神经元驱动持续行为，而 激活IOFC-纹状体投射神经元抑制持续行为。然而， 关于持续行为的差异调节机制的知识仍然存在 mOFC与IOFC的对比。该项目将使用化学发生和纤维光度技术在自由移动 小鼠以确定mOFC与IOFC内的神经元活动如何调节持续行为。我们将 用5-羟色胺1B受体（5-HT 1BR）激动剂急性激发诱导小鼠持续行为。 5-HT 1BR（以前在人体中称为5-HT 1D β）激动剂的药理学挑战加剧 强迫症患者的症状同样，我们发现用5-HT 1BR激动剂急性治疗小鼠， 持续性行为，包括称为“路线刻板”的高度重复形式的过度运动，以及 延迟交替任务中的持续反应。这些5-HT 1BR激动剂介导的作用可以是 通过对强迫症唯一有效的单一疗法，即4周的SRI慢性治疗来预防。因此，急性5- HT 1BR激动剂治疗诱导小鼠与强迫症相关的持续行为。我们将联合收割机纤维 光度学和化学遗传学与我们行之有效的行为方法，以确定机制 这是mOFC与IOFC对持续行为的差异控制的基础。以往报告的工作 mOFC-腹内侧纹状体投射的光遗传学刺激诱导小鼠的持续梳理， 而其他研究表明，光遗传学刺激IOFC-中央纹状体投射抑制 坚持不懈的梳理在这里，我们将评估化学发生抑制神经元投射的影响， 在5-HT 1BR激动剂诱导的持续性高血压中，mOFC与IOFC在纹状体中央内侧区的分布差异不显著。 行为我们还将确定持续行为是否与不同的变化有关， 使用GRAB 5-HT，5-羟色胺释放到mOFC中与IOFC中，和/或 mOFC与IOFC内的GABA能中间神经元或眶纹状体投射神经元。由于功能障碍 在眶额-纹状体回路内，多巴胺能系统也与神经性厌食症、成瘾性 和自闭症谱系障碍，我们的发现将广泛适用于许多条件。

PROJECT SUMMARY/ABSTRACT: Perseverative behaviors are prominent, disabling, and often treatment- resistant symptoms of several neuropsychiatric disorders including Obsessive Compulsive Disorder (OCD). Perseverative behavior refers to the repetition or continuation of a response that no longer results in a reward or expected outcome. Human neuroimaging data has associated abnormal activity within orbitofronto-striatal circuits with perseverative behavior in OCD patients. While early human neuroimaging studies identified overactivation of the entire orbitofrontal cortex (OFC), more recent studies have linked overactivation of the lateral OFC (lOFC) and hypoactivity of the medial OFC (mOFC) with OCD symptoms. Furthermore, preclinical work in rodents suggests that activating mOFC-striatal projection neurons drives perseverative behavior, while activating lOFC-striatal projection neurons suppresses perseverative behavior. Yet, a substantial gap in knowledge remains regarding the mechanisms underlying the differential regulation of perseverative behavior by the mOFC versus lOFC. This project will use chemogenetic and fiber photometry technologies in freely moving mice to determine how neuronal activity within the mOFC versus lOFC regulate perseverative behaviors. We will induce perseverative behavior in mice using acute challenge with a serotonin 1B receptor (5-HT1BR) agonist. Pharmacological challenge with agonists for the 5-HT1BR, previously termed 5-HT1Dβ in humans, exacerbates symptoms in OCD patients. Similarly, we found that treating mice acutely with a 5-HT1BR agonist induces perseverative behaviors including a highly repetitive form of hyperlocomotion termed “route stereotypy”, and perseverative responding in a delayed alternation task. These 5-HT1BR agonist-mediated effects can be prevented by the only effective monotherapy for OCD, 4 weeks of chronic treatment with SRIs. Thus, acute 5- HT1BR agonist treatment induces perseverative behaviors in mice with relevance to OCD. We will combine fiber photometry and chemogenetics with our well-validated behavioral methods to identify the mechanisms underlying the differential control over perseverative behavior by the mOFC versus lOFC. Previous work reported that optogenetic stimulation of mOFC-ventromedial striatal projections induces perseverative grooming in mice, while other work showed that optogenetic stimulation of lOFC-centromedial striatal projections suppresses perseverative grooming. Here, we will assess the effects of chemogenetic inhibition of neuronal projections from the mOFC versus lOFC to a large centromedial striatal region on 5-HT1BR agonist-induced perseverative behavior. We will also determine whether perseverative behavior is associated with differential changes in serotonin release into the mOFC versus lOFC using GRAB5-HT, and/or differential changes in the activity of GABAergic interneurons or orbitostriatal projection neurons within the mOFC versus lOFC. Since dysfunction within orbitofrontal-striatal circuits and the serotonergic system is also implicated in anorexia nervosa, addictive disorders, and autism spectrum disorders, our findings will be broadly applicable to a number of conditions.