Defining the Autonomic Cerebellum in Autism

项目摘要/摘要 自闭症谱系障碍(ASD)是一种普遍存在的致残性神经发育障碍，需要 对患者、他们的家人和国家经济造成重大损失。目前尚无针对性的治疗方法。 调节失调的自主神经反应，或称自主神经失调，影响并致残超过70%的自闭症儿童。多数 目前的医学方法是非选择性的，无效的，并与副作用相关。因此，一部小说和 ASD患者难治性自主神经功能障碍亟需靶向治疗。鉴于自主性障碍被认为是 从大脑如何调节外周自主器官的问题开始，进步的一个主要障碍是 对影响外周自主神经输出的神经网络的认识不全面。最近，我 确定了小脑对肾上腺髓质下行控制的主要来源，以及 释放肾上腺素并启动全身交感反应的自主器官。小脑 受累与临床相关，因为自主神经功能障碍和小脑异常都存在于ASD中。 小脑的浅表位置使其成为无创经颅磁的一个有吸引力的目标 刺激(TMS)。然而，两个剩余的知识差距阻碍了临床翻译：我们不知道哪些网站 ‘自主小脑’影响自主神经紊乱的生理反应，以及这些 在ASD这样的情况下，部位会受到影响，这些情况下存在自主神经功能障碍和小脑异常。这个 这个项目的目标是通过定义自主神经小脑的区域来填补这些空白 控制生理反应，并通过测试自闭症模型中这些小脑网络是如何改变的。 具体地说，目标1是测试调节肾上腺相关小脑是否会改变自主神经生理。 回应。目的2是检测ASD的绒猴模型中自主神经反应是否异常。目标3是测试 如果控制肾上腺交感神经输出的小脑部位在ASD的绒猴模型中发生改变。我 将采用体内记录狂犬病病毒的自主神经生理反应和跨神经元传输来 为自主性小脑如何受到影响建立行为学和系统神经学基础 ASD.这些研究有可能确定特定的小脑区域作为新治疗的靶点。 旨在使ASD难治性自主神经功能障碍正常化的方法(例如，小脑TMS)。因此， 拟议中的工作可能最终改变我们处理自闭症和其他相关疾病的自主神经障碍的方式 有小脑异常。

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a prevalent and disabling neurodevelopmental disorder that takes a significant toll on patients, their families, and the national economy. There are no targeted treatments for the dysregulated autonomic responses, or dysautonomia, that affect and disable over 70% of autistic children. Most current medical approaches are non-selective, ineffective, and associated with side effects. Thus, a novel and targeted therapy is urgently needed for refractory dysautonomia in ASD. Given dysautonomia is thought to arise from a problem in how the brain regulates peripheral autonomic organs, a major barrier to progress has been an incomplete understanding of the neural networks that influence peripheral autonomic output. Recently, I identified the sites of the cerebellum that are major sources of descending control over the adrenal medulla, an autonomic organ that releases adrenaline and initiates the body-wide sympathetic response. Cerebellar involvement is clinically relevant because dysautonomia and cerebellar abnormalities are both present in ASD and the superficial location of the cerebellum makes it an attractive target for non-invasive trans-cranial magnetic stimulation (TMS). Yet, two remaining knowledge gaps prevent clinical translation: we do not know which sites of the ‘autonomic cerebellum’ influence the physiologic responses perturbed in dysautonomia and how these sites are affected in conditions like ASD where dysautonomia and cerebellar abnormalities are present. The goals of this project are to fill these gaps by defining the regions of the autonomic cerebellum that selectively control physiologic responses and by testing how these cerebellar networks are altered in a model of autism. Specifically, Aim 1 is to test if modulating the adrenal-related cerebellum alters autonomic physiologic responses. Aim 2 is to test if autonomic responses are abnormal in a marmoset model of ASD. Aim 3 is to test if the cerebellar sites that control the adrenal’s sympathetic output are altered in a marmoset model of ASD. I will employ in vivo recording of autonomic physiologic responses and trans-neuronal transport of rabies virus to establish the behavioral and systems neuroscience foundations for how the autonomic cerebellum is affected in ASD. These studies have the potential to identify specific cerebellar regions to target with a new treatment approach (e.g., cerebellar TMS) that aims to normalize refractory dysautonomia in ASD. Thus, the results of the proposed work may ultimately transform how we manage dysautonomia in ASD and other disorders associated with cerebellar abnormalities.