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.

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.