Impact of autism genetic risk on cortical sensorimotor dynamics

自闭症遗传风险对皮质感觉运动动力学的影响

• 批准号: 10750315
• 负责人: Randall M. Golovin
• 金额: $ 6.95万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750315
• 关键词: ASD patient; Affect; Animals; Area; Behavior; Behavioral; Brain; Calcium; Clinical; Clothing; Code; Cognition; Cognitive; Cognitive deficits; Data; Defect; Detection; Diagnosis; Disease; Dorsal; Exhibits; Fellowship; Foundations; Functional disorder; Gene Mutation; Genes; Genetic; Genetic Risk; Goals; Heterozygote; Human; Image; Impaired cognition; Impairment; Intellectual functioning disability; Laboratory Research; Learning; Measures; Mental disorders; Monitor; Motor Cortex; Motor output; Mus; Mutation; National Research Service Awards; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Neurosciences; Operant Conditioning; Output; Patients; Performance; Phenotype; Population; Prosencephalon; Regulation; Reporting; Research; Role; Running; SYNGAP1; Sensory; Signal Transduction; Skin; Surface; System; Tactile; Task Performances; Testing; Texture; Touch sensation; Training; Variant; Vibrissae; Work; autism spectrum disorder; autistic; behavioral impairment; career; cognitive control; cognitive function; cognitive performance; comorbidity; experimental study; functional plasticity; genetic risk factor; learned behavior; loss of function; maladaptive behavior; mouse model; predictive modeling; protein function; repetitive behavior; response; risk variant; sensory cortex; sensory input; sensory stimulus; sensory system; social deficits; stem; therapy development; tool

Project Summary Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder defined by social deficits and restricted and repetitive behaviors. These behaviors have been associated with impaired sensory processing and sensorimotor integration. In addition, ASD is often comorbid with intellectual disability (ID) and cognitive impairment. This is especially true of ASD diagnoses associated with one of several major ASD risk genes. While it is well established that sensory processing is critical for cognitive function in general and learning in particular, it is not clear how deficits in sensory processing in ASD may contribute to cognitive and learning impairments in patients. I hypothesize that learning impairments in ASD patients stem from sensory processing deficits leading to a disruption in cortical functional connectivity critical for learned behaviors. I will test this idea by using a mouse model of major ASD genetic risk that shows a tactile instrumental learning impairment. Importantly, learning deficits require the function of the ASD risk gene in cortical excitatory projection neurons (see preliminary data) highlighting the importance for cortical processing in this phenotype. In addition, these animals have a reduced cortical response to touch. In Aim 1, I will assess the impact of the ASD risk gene on sensory processing in dorsal cortex by monitoring calcium dynamics as mice receive passive sensory stimulation. In addition, I will manipulate the ASD risk gene in sensory cortex to test its autonomous control of calcium dynamics and connectivity. I expect that the ASD risk gene model mice will have reduced responses in sensory cortex and disrupted functional connectivity to downstream regions in dorsal cortex. In Aim 2, I will monitor dorsal cortex calcium dynamics as mice perform an instrumental learning task to test the idea that the major ASD risk gene causes altered dynamics of cortical functional connectivity. Furthermore, I will determine to what extent putative mesoscale connectivity deficits in the mouse model predict learning impairments in the task. Lastly, I will specifically manipulate the ASD risk gene in sensory cortex to tests its autonomous role in regulating functional connectivity during learning. The impact of this proposal will be to understand the neurobiological underpinnings of impaired learning related to a major ASD risk gene, which may serve to inform the development of treatments for cognitive deficits in ASD patients. In conclusion, I am an excellent candidate for a National Research Service Award Fellowship because of my background in ASD risk gene research and the training in cutting-edge systems neuroscience tools provided by the Rumbaugh lab. Altogether, the training and experiments proposed here will enable me to further our understanding of ASD and lay a strong foundation for my career goal of running an independent research laboratory.

项目摘要 自闭症谱系障碍（ASD）是一种由社会缺陷和受限制定义的神经发育障碍 和重复行为。这些行为与感官处理受损有关 感觉运动积分。此外，ASD通常与智力残疾（ID）和认知合并 损害。与几个主要ASD风险基因之一相关的ASD诊断尤其如此。 尽管有很好的确定，感官处理对于一般的认知功能至关重要，并且在 特别是，尚不清楚ASD中的感觉处理中的缺陷如何有助于认知和学习 患者的障碍。我假设ASD患者的学习障碍源于感觉处理 缺陷导致对学习行为至关重要的皮质功能连通性的破坏。我会测试这个想法 通过使用主要ASD遗传风险的小鼠模型，该模型显示出触觉仪器学习障碍。 重要的是，学习缺陷需要在皮质兴奋性投射神经元中ASD风险基因的功能 （请参阅初步数据）强调此表型中皮质加工的重要性。另外，这些 动物的皮质反应减少了。在AIM 1中，我将评估ASD风险基因对 通过监测钙动力学，随着小鼠接收被动感觉，在背皮层中的感觉处理 刺激。此外，我将操纵感觉皮层中的ASD风险基因，以测试其对 钙动力学和连通性。我预计ASD风险基因模型小鼠的反应将减少 感觉皮层和背侧皮层下游区域的功能连通性破坏。在AIM 2中，我会 监视背皮层钙动力学，因为小鼠执行一项工具性学习任务，以测试以下想法 主要的ASD风险基因导致皮质功能连通性的动力学改变。此外，我将确定 鼠标模型中假定的中尺度连通性缺陷在多大程度上预测了学习障碍 任务。最后，我将在感觉皮层中专门操纵ASD风险基因，以测试其在 在学习过程中调节功能连接。该提案的影响是了解 与主要ASD风险基因有关的学习受损的神经生物学基础，该基因可能有助于 告知ASD患者认知缺陷治疗的发展。总之，我是一个很好的 由于我的ASD风险基因背景，国家研究服务奖奖学金奖学金 Rumbaugh实验室提供的研究和尖端系统神经科学工具的培训。 总之，这里提出的培训和实验将使我能够进一步了解ASD和ASD 为我的职业目标奠定了一个独立研究实验室的目标。