Look inward: brainstem and cortical circuits for boosting interoceptive attention

项目总结/摘要 一个巨大的努力，以检查外围和中央大脑回路的基础外部感官，如视觉， 听觉和触觉听觉产生了广泛的见解，并推动了各种感觉康复的发展 治疗相反，对大脑如何接收和处理信号的类似机械理解 是非常缺乏的这是令人惊讶的，因为人们越来越意识到， 在神经病学、精神病学和普通医学的广泛疾病中的体脑通信 (e.g.抑郁和焦虑障碍;自闭症谱系障碍;周边状态下的病态行为 感染/炎症，如疲劳，减少消费，社会孤立和快感缺乏;进食 疾病和肥胖症;心血管疾病、胃肠道疾病、睡眠呼吸暂停和其他呼吸系统疾病 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）。一个控制我们感知和选择性注意力的特定回路的路线图， 这些身体信号可以产生许多精确的靶向临床治疗。然而，少校 技术挑战限制了对内部感觉进行良好控制研究的可能性， 感知和注意力的动物模型。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详细的电路级理解， 内感受-注意和感知内部身体信号的过程-以及这是如何发生的。 在一系列疾病中，这一过程被打乱。我将利用我的专业知识创新新的战略， 研究视觉、听觉和触觉的电路层次基础，以开发一个多层次的平台， 研究行为小鼠的内感受。特别是，我们将克服以下关键挑战。一是 将开发一种新的操作性行为模式，在这种模式中，头部受限的小鼠学会报告特定的 阈值级身体信号。为了准确测量特定身体信号的感知阈值，我们将 光遗传学刺激特定的遗传定义的迷走传入神经元组， 特定的身体器官（例如肺伸展或肠道营养信号）到大脑。通过不同强度的刺激， 我们将估计内感受性感知阈值，这些阈值如何随着学习而提高（类似于 正念和冥想训练）以及它们在竞争性外部刺激（例如， 闪光的手机）。然后，我们将开始剖析控制特定神经元中央处理的神经回路。 迷走神经信号为此，我们将联合收割机将上述行为与光遗传学的新方法结合起来 操作和双光子钙成像（i）迷走神经传入的中枢末梢，（ii）脑干 迷走神经传入传递的神经元输入和（iii）岛叶皮层神经元（与 人类的内感受性注意力）。总之，这个强大的遗传模型系统将提供急需的 健康和疾病中内感受的细胞、回路和行为研究之间的联系。

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.