Defining the Autonomic Cerebellum in Autism

定义自闭症自主小脑

• 批准号: 10696307
• 负责人: Ronald Robert Seese
• 金额: $ 39万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696307
• 关键词: Adrenal Glands; Adrenal Medulla; Affect; Anatomy; Animals; Area; Award; Behavior; Behavioral; Blood Pressure; Brain; Brain region; Budgets; Callithrix; Cerebellar vermis structure; Cerebellum; Clinical; Communities; Core Facility; Dedications; Development; Disease; Dysautonomias; Educational process of instructing; Ensure; Epinephrine; Exhibits; Exposure to; Extramural Activities; Faculty; Family; Foundations; Funding; Galvanic Skin Response; Goals; Heart Rate; Human; Institution; Knowledge; Length; Lobule; Location; Medical; Mentors; Mentorship; Modeling; Molecular; Monkeys; Neuroanatomy; Neurobiology; Neurodevelopmental Disorder; Neurologist; Neurology; Neurosciences; Nurses; Ohio; Organ; Output; Patients; Pediatric Hospitals; Pediatrics; Peer Review; Peripheral; Physiological; Productivity; Psychiatry; Publications; Rabies virus; Refractory; Research; Research Assistant; Research Training; Resources; Risk; Science; Secure; Site; Source; System; Testing; Transcranial magnetic stimulation; Translating; Universities; Valproic Acid; Vision; Work; animal facility; autism spectrum disorder; autistic children; clinical training; clinical translation; clinically relevant; density; design; disability; faculty mentor; graduate student; in vivo; individuals with autism spectrum disorder; innovative technologies; member; multidisciplinary; neural network; neuronal transport; neuroregulation; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; prenatal exposure; prevent; programs; response; senior faculty; side effect; skills; square foot; targeted treatment; tenure track; therapeutic target; translational research program; waiver

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.

项目摘要/摘要 自闭症谱系障碍（ASD）是一种普遍且残疾的神经发育障碍，患有 对患者，家人和国民经济的重大损失。没有针对性的治疗方法 影响超过70％的侵略性儿童的自主反应或功能障碍的自主反应失调。最多 当前的医学方法是非选择性，无效的，并且与副作用有关。那是一本小说和 迫切需要靶向治疗的ASD难治性动作障碍。鉴于功能障碍被认为会出现 从大脑如何调节外围自主器官的问题中，进步的主要障碍一直是 对影响周边自主产量的神经网络的不完全理解。最近，我 鉴定出小脑的部位是对肾上腺髓质下降的主要来源 释放肾上腺素并启动身体范围的交感反应的自主器官。小脑 参与在临床上是相关的，因为ASD中存在性障碍和小脑异常 小脑的表面位置使其成为非侵入性跨颅磁的吸引力的目标 刺激（TMS）。然而，剩下的两个知识差距阻止了临床翻译：我们不知道哪些站点 “自主小脑”影响了动作障碍的生理反应，以及如何这些反应 在诸如ASD等条件下，存在性障碍和小脑异常。这 该项目的目标是通过定义自主小脑的区域来填补这些空白 控制生理反应并测试这些小脑网络如何在自闭症模型中改变。 具体而言，目标1是测试是否调节肾上腺相关小脑会改变自主生理学 回答。 AIM 2是测试ASD的Marmoset模型中的自主响应是否异常。目标3是测试 如果在ASD的Marmoset模型中改变了控制肾上腺交感输出的小脑位点。我 将利用体内记录自主生理反应和狂犬病病毒的跨神经元转运 建立行为和系统神经科学基础，以如何影响自主的小脑 ASD。这些研究有可能识别特定的小脑区域，以采用新的治疗方法 旨在使ASD中难治性的功能障碍归一化的方法（例如Cerebellar TMS）。那，结果 拟议的工作最终可能会改变我们如何管理ASD和其他相关疾病中的功能障碍 小脑异常。