Development, Function, and Dysfunction of Gastrointestinal Tract-Innervating Dorsal Root Ganglia Neurons in Autism Spectrum Disorder

自闭症谱系障碍中胃肠道支配的背根神经节神经元的发育、功能和功能障碍

• 批准号: 10584142
• 负责人: Lauren Lynn Orefice
• 金额: $ 38.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584142
• 关键词: Afferent Neurons; Anatomy; Anxiety; Axon; Biological Assay; Brain; Brain Stem; Cells; Central Nervous System; Child; Chronic; Colon; Colorectal; Conscious; DNA Sequence Alteration; Data; Development; Disease model; Electrophysiology (science); Environment; Environmental Risk Factor; Esthesia; Etiology; Exhibits; Functional disorder; Gastrointestinal Motility; Gastrointestinal tract structure; Gene Mutation; Genes; Genetic; Goals; Histology; Impairment; In Vitro; Lead; Lifestyle-related condition; Light; Limb structure; Link; Measures; Mechanics; Methyl-CpG-Binding Protein 2; Modality; Modeling; Mus; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Nodose Ganglion; Pain; Pathology; Pathway interactions; Patients; Peripheral; Permeability; Phenotype; Population; Prevalence; Process; Property; Rectum; Reflex action; Reporting; Role; Sensory; Severities; Signal Transduction; Site; Skin; Social Behavior; Social Interaction; Spinal; Spinal Cord; Spinal Ganglia; Stereotyped Behavior; Stretching; Symptoms; Tactile; Testing; Touch sensation; Unconscious State; Vagus nerve structure; Vertebral column; Viscera; Visceral pain; Withdrawal; Work; anxiety-like behavior; associated symptom; autism spectrum disorder; developmental disease; dysbiosis; gastrointestinal; gastrointestinal function; gastrointestinal system; gut dysbiosis; gut microbiome; improved; in vivo; individuals with autism spectrum disorder; mechanical force; microbial; microbiome alteration; motility disorder; mouse genetics; mouse model; neural circuit; neurotransmission; novel; pain behavior; pain signal; rectal; reduce symptoms; repetitive behavior; response; sensory stimulus; social; social anxiety; social communication; social deficits; stereotypy; stressor; treatment strategy

Project Summary: Autism spectrum disorders (ASDs) are prevalent developmental disorders, defined by impairments in social interactions and communication as well as restricted, repetitive behaviors. The majority of individuals with ASD exhibit a range of co-morbid symptoms, including gastrointestinal (GI) dysfunction. Up to 91% of people with ASD have chronic GI problems, and GI issues are emphasized as major concerns by patients and clinicians. GI dysfunction is thought to contribute to core ASD symptoms, as patients with chronic GI pain exhibit increased social withdrawal, irritability, and stereotyped behaviors. Despite the prevalence and impact of GI issues in ASD, little is known regarding the extrinsic neural circuits that modulate GI function, the etiology of GI abnormalities in ASD, and whether GI deficits are mechanistically linked to core ASD symptoms. Sensory information from the gut is conveyed to the central nervous system (CNS) by two extrinsic pathways of vagal and spinal sensory afferents whose cell bodies are within the nodose and dorsal root ganglia (DRG), respectively. GI-innervating DRG neurons are critical for normal GI function, yet little is known about the development and function of these neurons. Further, we have little understanding of how GI signals are encoded, processed, and represented in the spinal cord. In our prior studies, we found that DRG neurons are key sites at which ASD-associated gene mutations have a critical impact. We showed how aberrant function of DRG neurons that innervate the skin cause over- reactivity to light touch, and can link multiple ASD phenotypes, including social deficits and anxiety-like behaviors. We hypothesize that similar over-reactivity to ‘viscerosensory’ signals from the GI system contributes to ASD symptoms. We further hypothesize that these DRG neurons that connect the GI tract and CNS are critical sites of dysfunction in ASD. While significant progress has been made to understand brain-specific mechanisms and circuits underlying ASD pathology, there is a substantial need to understand the contributions of peripheral neuron and spinal cord circuit disruptions to ASD phenotypes. This proposal aims to investigate the development and function of GI-innervating DRG neurons and determine the mechanisms through which a key sensory modality, viscerosensation of the GI tract, may be altered in mouse models for ASD. Our first goal is to characterize the development and function of colon- innervating DRG neurons, and determine whether ASD-associated gene mutations cause anatomical and functional disruptions to colon-innervating DRG neurons. Our second goal is to investigate whether DRG neuron dysfunction triggers abnormal GI function, aberrant encoding of GI signals in the spinal cord, and increased GI pain in mouse models for ASD. Lastly, we will test whether test whether a combination of environmental factors (gut dysbiosis) and genetic factors (ASD-associated gene mutations) results in GI-innervating DRG neuron dysfunction and GI pain, and ultimately, contributes to anxiety-like behaviors and social impairments in ASD.

项目摘要：自闭症谱系障碍 (ASD) 是一种普遍存在的发育障碍，定义为 社交互动和沟通障碍以及受限的重复行为。 自闭症谱系障碍 (ASD) 患者表现出一系列共病症状，包括胃肠道 (GI) 功能障碍。 91% 的自闭症谱系障碍患者患有慢性胃肠道问题，并且胃肠道问题被患者视为主要关注的问题 胃肠道功能障碍被认为是导致自闭症谱系障碍核心症状的原因之一，因为患有慢性胃肠道疼痛的患者 尽管社交退缩、易怒和刻板行为普遍存在，但其影响却有所增加。 自闭症谱系障碍 (ASD) 中的胃肠道问题，对于调节胃肠道功能的外在神经回路、其病因学知之甚少 自闭症谱系障碍中的胃肠道异常，以及胃肠道缺陷是否与自闭症谱系障碍的核心症状有机械联系。 来自肠道的感觉信息通过两种外在信息传递到中枢神经系统（CNS） 迷走神经和脊髓感觉传入的通路，其细胞体位于结节和背根神经节内 （DRG），分别支配胃肠道的 DRG 神经元对于正常的胃肠道功能至关重要，但人们对此知之甚少。 此外，我们对胃肠道信号的编码方式知之甚少。 处理并在脊髓中表现出来。 在我们之前的研究中，我们发现DRG神经元是ASD相关基因突变的关键位点 我们展示了支配皮肤的 DRG 神经元的异常功能如何导致过度。 对轻触的反应，并且可以将多种 ASD 表型联系起来，包括社交缺陷和焦虑样 我们研究了对胃肠道系统“内脏感觉”信号的类似过度反应。 我们进一步发现，这些连接胃肠道和中枢神经系统的 DRG 神经元至关重要。 尽管在了解自闭症谱系障碍（ASD）的功能障碍部位方面已经取得了重大进展。 和自闭症谱系障碍 (ASD) 病理学背后的电路，非常需要了解外周的贡献 神经元和脊髓回路中断对 ASD 表型的影响。 该提案旨在研究 GI 神经支配 DRG 神经元的发育和功能以及 确定关键的感觉方式（胃肠道的内脏感觉）可能通过的机制 我们的首要目标是描述自闭症谱系障碍 (ASD) 小鼠模型的结肠发育和功能特征。 神经支配 DRG 神经元，并确定 ASD 相关基因突变是否导致解剖学和 我们的第二个目标是研究 DRG 神经元是否受到结肠神经支配的功能破坏。 功能障碍会引发胃肠道功能异常、脊髓中胃肠道信号编码异常以及胃肠道增加 最后，我们将测试 ASD 小鼠模型的疼痛是否与环境因素相结合。 （肠道菌群失调）和遗传因素（ASD 相关基因突变）导致胃肠道神经支配 DRG 神经元 功能障碍和胃肠道疼痛，最终导致自闭症谱系障碍的焦虑样行为和社交障碍。