Look inward: brainstem and cortical circuits for boosting interoceptive attention

向内看：脑干和皮质回路增强内感受注意力

• 批准号: 10457412
• 负责人: Mark L Andermann
• 金额: $ 122.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457412
• 关键词: Acute Pain; Afferent Neurons; Anhedonia; Animal Model; Anorexia Nervosa; Anxiety; Anxiety Disorders; Arthrogryposis; Attention; Auditory; Awareness; Behavior; Behavioral Paradigm; Biological Models; Brain; Brain Stem; Calcium; Cardiovascular Diseases; Cellular Phone; Clinical; Communication; Consumption; Controlled Study; Development; Disease; Eating Disorders; Esthesia; Fatigue; Gastrointestinal Diseases; Genetic Models; Goals; Head; Health; Hearing; Human; Image; Infection; Inflammation; Interoception; Irritable Bowel Syndrome; Learning; Link; Lung; Measures; Medicine; Mental Depression; Mus; Nausea and Vomiting; Neurology; Neuromodulator; Neurons; Nutrient; Obesity; Organ; Pain; Perception; Peripheral; Process; Pruritus; Psychiatry; Rehabilitation therapy; Reporting; Respiration Disorders; Role; Sensory; Signal Transduction; Sleep Apnea Syndromes; Social isolation; Stimulus; Stretching; Sudden infant death syndrome; Tactile; Touch sensation; Training; Vision; Visual; autism spectrum disorder; behavioral study; chemotherapy; chronic pain; improved; innovation; insight; mindfulness meditation; mouse genetics; neural circuit; novel; novel strategies; optogenetics; respiratory; selective attention; transmission process; two-photon

Project Summary/Abstract A vast effort to examine peripheral and central brain circuits underlying external senses such as vision, hearing and touch hearing has yielded broad insights and fueled development of diverse sensory rehabilitation therapies. In contrast, a similar mechanistic understanding of how the brain receives and attends to signals from inside the body is sorely lacking. This is surprising given the growing awareness of the central roles of body-brain communication in a broad range of diseases spanning neurology, psychiatry, and general medicine (e.g. depression and anxiety disorders; autism spectrum disorder; sickness behaviors during peripheral states of infection/inflammation such as fatigue, decrease consumption, social isolation, and anhedonia; eating disorders and obesity; cardiovascular diseases, gastrointestinal diseases, sleep apnea and other respiratory disorders, itch, acute and chronic pain, irritable bowel syndrome, and natural and chemotherapy-induced nausea and vomiting). A roadmap of the specific circuits governing our perception and selective attention to these body signals could give rise to a host of precisely targeted clinical therapies. However, major technological challenges have limited the possibility of well-controlled studies of internal sensation, perception and attention in animal models. Here, I propose to overcome these technical barriers to establish a platform that will enable our lab and others to gain a detailed circuit-level understanding of interoception – the process of attending to and perceiving internal bodily signals – and how this process is disrupted across a range of diseases. I will use my expertise in innovating new strategies for studying the circuit-level basis of visual, auditory and tactile perception to develop a multi-level platform for studying interoception in behaving mice. In particular, we will overcome the following key challenges. First, we will develop a novel operant behavioral paradigm in which head-restrained mice learn to report specific threshold-level body signals. To accurately measure thresholds for perception of specific body signals, we will optogenetically stimulate specific genetically-defined sets of vagal afferent neurons that relay signals from specific body organs (e.g. lung stretch or gut nutrient signals) to the brain. By stimulating at various intensities, we will estimate interoceptive perceptual thresholds, how these thresholds improve with learning (similar to mindfulness and meditation training) and how they worsen in the presence of competing external stimuli (e.g. a flashing cell phone). We will then begin to dissect the neural circuits that gate central processing of specific vagal signals. To this end, we will combine the above behaviors with new approaches for optogenetic manipulation and two-photon calcium imaging of (i) central terminals of vagal afferents, (ii) brainstem serotonergic inputs to regulating vagal afferent transmission and (iii) neurons in insular cortex (implicated in interoceptive attention in humans). Together, this powerful genetic model system will provide a much-needed link between cellular, circuit and behavioral studies of interoception in health and disease.

项目摘要/摘要 巨大的努力来检查外围和中央大脑电路，例如视觉，例如视觉， 听力和触摸听证会带来广泛的见解，并助长了潜水员感官康复的发展 疗法。相比之下，对大脑如何接收和参加信号的类似机械理解 从身体内部严重缺乏。鉴于人们对核心角色的核心意识越来越令人惊讶 跨越神经病学，精神病学和通用医学的广泛疾病中的身体脑沟通 （例如抑郁和动画障碍；自闭症谱系障碍；外周状态下的疾病行为 感染/炎症，例如疲劳，减少消费，社会隔离和狂热；吃 疾病和肥胖；心血管疾病，胃肠道疾病，睡眠呼吸暂停和其他呼吸道 疾病，瘙痒，急性和慢性疼痛，肠易激综合征以及自然和化学疗法诱导的 恶心和呕吐）。管理我们的看法和选择性关注的特定电路路线图 这些身体信号可能导致许多精确靶向的临床疗法。但是，主要 技术挑战限制了对内部感觉进行良好控制的可能性， 动物模型中的感知和关注。在这里，我建议克服这些技术障碍 建立一个平台，使我们的实验室和其他人能够获得对电路级的详细理解 拦截 - 参与和感知内部身体信号的过程 - 如何 过程中各种疾病的过程被破坏。我将使用我的专业知识来创新新策略 研究视觉，听觉和触觉感知的电路级基础，以开发一个多层次平台 研究行为小鼠中的感受。特别是，我们将克服以下主要挑战。首先，我们 将开发出一种新颖的操作行为范式，在该行为范式中，头部缠身的小鼠学会报告特定 阈值级的身体信号。为了准确测量特定身体信号感知的阈值，我们将 通过光源刺激特定的遗传定义的迷走神经神经元，这些神经元从 特定的身体器官（例如肺伸展或肠道营养信号）。通过刺激各种强度， 我们将估算互感的感知阈值，这些阈值如何通过学习提高（类似于 正念和冥想训练）以及他们如何在存在竞争的外部刺激的情况下担心（例如 闪烁的手机）。然后，我们将开始剖析特定门中心处理的神经回路 迷走神经信号。为此，我们将上述行为与新方法相结合 （i）迷走神经传入的中央终端的操纵和两光子钙成像，（ii）脑干 血清素能输入以调节岛状皮质中的迷走神经传播和（iii）神经元（与 在人类中的感知性关注）。这种强大的遗传模型系统将提供急需的 健康和疾病中互感的细胞，电路和行为研究之间的联系。