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: 10679014
• 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/10679014
• 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; Meditation; 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; Technology; Touch sensation; Training; Vision; Visual; autism spectrum disorder; behavioral study; bodily sensation; chemotherapy; chronic pain; improved; innovation; insight; mindfulness; mouse genetics; neural circuit; novel; novel strategies; optogenetics; respiratory; restraint; 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 这是一项巨大的努力，旨在研究视觉等外部感觉背后的外周和中央大脑回路， 听觉和触觉听力产生了广泛的洞察力，并推动了各种感觉康复的发展 治疗。相比之下，对大脑如何接收和处理信号的机械理解类似 从身体内部来看，是非常缺乏的。这是令人惊讶的，因为人们越来越意识到 涵盖神经学、精神病学和普通医学的多种疾病中的体脑交流 (例如抑郁症和焦虑症；自闭症谱系障碍；外周状态下的疾病行为 指感染/炎症，如疲倦、消耗减少、社交孤立和快感缺乏；进食 疾病与肥胖；心血管疾病、胃肠疾病、睡眠呼吸暂停及其他呼吸系统疾病 疾病，瘙痒，急性和慢性疼痛，肠易激综合征，以及自然和化疗引起的 恶心和呕吐)。指导我们感知和选择性注意的特定回路的路线图 这些身体信号可能会产生一系列精确定向的临床疗法。然而，梅杰 技术挑战限制了对内在感觉进行良好控制研究的可能性， 动物模型中的感知和注意。在这里，我建议克服这些技术障碍，以 建立一个平台，使我们的实验室和其他人能够详细了解电路级别的 内感--注意和感知身体内部信号的过程--以及这是如何 这一过程会因一系列疾病而中断。我将利用我的专业知识创新新战略，以 研究视觉、听觉和触觉的电路级基础，开发多层次的平台 研究表现良好的小鼠的内感。特别是，我们将克服以下关键挑战。首先，我们 将开发一种新的可操作的行为范式，在这种范式中，头束缚小鼠学习报告特定的 阈值级别的身体信号。为了准确测量感知特定身体信号的阈值，我们将 光遗传刺激特定的遗传定义的迷走神经传入神经元集合，传递来自 特定的身体器官(例如，肺伸展或肠道营养信号)传递给大脑。通过不同强度的刺激， 我们将估计内感知觉阈值，这些阈值如何随着学习而提高(类似于 正念和冥想训练)，以及它们在相互竞争的外部刺激(例如 闪烁的手机)。然后我们将开始剖析控制特定脑区中央处理的神经回路。 迷走神经信号。为此，我们将把上述行为与光遗传的新方法结合起来 (I)迷走神经传入中枢末梢、(Ii)脑干的手法和双光子钙成像 5-羟色胺能输入调节迷走神经传入传递和(Iii)岛叶皮质神经元(涉及 人类的联觉注意)。这一强大的遗传模型系统将共同提供亟需的 健康和疾病内感的细胞、回路和行为研究之间的联系。