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

剖析内侧与外侧眶额回路活动在持续行为中的作用

• 批准号: 10665272
• 负责人: STEPHANIE C DULAWA
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665272
• 关键词: Acute; Address; Agonist; Anorexia Nervosa; Behavior; Behavioral; Chronic; Corpus striatum structure; Data; Fiber; Functional disorder; Genetic; Genetic study; Grooming; Human; Interneurons; Knowledge; Lateral; Link; Locomotion; Medial; Mediating; Methods; Mus; Neurons; Obsessive-Compulsive Disorder; Outcome; Patients; Photometry; Regulation; Reporting; Resistance; Rewards; Rodent; Role; Route; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Serotonin Receptor 5-HT1B; Signal Transduction; Symptoms; Technology; Testing; Work; addiction; autism spectrum disorder; awake; hippocampal pyramidal neuron; neural; neuroimaging; neuropsychiatric disorder; novel therapeutic intervention; optogenetics; pharmacologic; pre-clinical; preclinical study; prevent; response; stereotypy

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.

项目摘要/摘要：顽固行为是突出的、致残的，并且经常被治疗—— 包括强迫症（OCD）在内的多种神经精神疾病的顽固症状。 持续行为是指重复或继续某种不再带来奖励或奖励的反应。 人类神经影像数据与眶额纹状体内的异常活动相关。 早期人类神经影像学研究发现，强迫症患者存在持续行为的回路。 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 (mOFC) 活动减退，伴有强迫症症状。 对啮齿类动物的研究表明，激活 mOFC 纹状体投射神经元可驱动持续行为，而 激活 lOFC 纹状体投射神经元会抑制持续行为，但在这方面存在巨大差距。 关于持久行为的差异调节机制的知识仍然存在 由 mOFC 与 lOFC 进行比较 该项目将在自由移动中使用化学遗传学和光纤光度测量技术。 我们将使用小鼠来确定 mOFC 与 lOFC 内的神经活动如何调节持续行为。 使用血清素 1B 受体 (5-HT1BR) 激动剂进行急性激发，诱导小鼠持续行为。 5-HT1BR（以前在人类中称为 5-HT1Dβ）激动剂的药理学挑战恶化 同样，我们发现用 5-HT1BR 激动剂急性治疗小鼠会诱发症状。 持续的行为，包括高度重复的过度运动，称为“路线刻板印象”，以及 这些 5-HT1BR 激动剂介导的效应可能是延迟交替任务中的持续反应。 强迫症的唯一有效单一疗法是 4 周的 SRI 慢性治疗，因此，急性 5- 可以预防这种情况。 HT1BR 激动剂治疗会诱导小鼠出现与强迫症相关的持久行为，我们将结合纤维。 光度测定和化学遗传学与我们经过充分验证的行为方法来识别机制 mOFC 与 lOFC 对持续行为的不同控制是先前报告的工作的基础。 mOFC腹内侧纹状体投射的光遗传学刺激会诱导小鼠持续梳理毛发， 而其他工作表明，lOFC-中心内侧纹状体投射的光遗传学刺激会抑制 在这里，我们将评估化学遗传学抑制对神经元投射的影响。 mOFC 与 lOFC 对 5-HT1BR 激动剂诱导的持久性大中心内侧纹状体区域的影响 我们还将确定持续行为是否与差异变化相关。 使用 GRAB5-HT 比较 5-羟色胺释放到 mOFC 与 lOFC 中的情况，和/或活性的差异变化 mOFC 内的 GABA 能中间神经元或眶纹状体投射神经元与 lOFC 功能障碍相比。 眶额-纹状体回路和血清素系统也与神经性厌食症、成瘾性有关 障碍和自闭症谱系障碍，我们的研究结果将广泛适用于许多疾病。