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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要自闭症谱系障碍 (ASD) 是一种神经发育障碍，定义为社交缺陷和受限以及重复的行为。这些行为与感觉处理受损有关感觉运动整合。此外，自闭症谱系障碍 (ASD) 常常与智力障碍 (ID) 和认知障碍并存。损害。对于与几个主要 ASD 风险基因之一相关的 ASD 诊断尤其如此。虽然众所周知，感觉处理对于一般认知功能和学习至关重要特别是，目前尚不清楚自闭症谱系障碍患者的感觉处理缺陷如何促进认知和学习患者的损伤。我假设 ASD 患者的学习障碍源于感觉处理缺陷会导致对学习行为至关重要的皮质功能连接中断。我会测试这个想法通过使用具有主要自闭症谱系障碍遗传风险的小鼠模型，该模型显示出触觉工具学习障碍。重要的是，学习缺陷需要皮质兴奋性投射神经元中 ASD 风险基因的功能（参见初步数据）强调了这种表型中皮质处理的重要性。此外，这些动物对触摸的皮质反应减弱。在目标 1 中，我将评估 ASD 风险基因对当小鼠接受被动感觉时，通过监测钙动态来进行背皮层的感觉处理刺激。此外，我还将操纵感觉皮层中的 ASD 风险基因来测试其自主控制钙动力学和连接性。我预计 ASD 风险基因模型小鼠的反应会降低感觉皮层和背侧皮层下游区域的功能连接被破坏。在目标 2 中，我将当小鼠执行工具性学习任务时，监测背皮质钙动态，以测试主要的 ASD 风险基因会导致皮质功能连接的动态改变。此外，我将确定小鼠模型中假定的中尺度连通性缺陷在多大程度上可以预测小鼠的学习障碍任务。最后，我将专门操纵感觉皮层中的 ASD 风险基因来测试其自主作用。在学习过程中调节功能连接。该提案的影响将是了解学习障碍的神经生物学基础与一个主要的 ASD 风险基因有关，这可能有助于为 ASD 患者认知缺陷治疗的开发提供信息。总而言之，我是一个优秀的人由于我在 ASD 风险基因方面的背景，我成为国家研究服务奖奖学金的候选人朗博实验室提供的尖端系统神经科学工具的研究和培训。总而言之，这里提出的培训和实验将使我能够进一步了解 ASD 和为我经营独立研究实验室的职业目标奠定了坚实的基础。