Impact of autism genetic risk on cortical sensorimotor dynamics

项目摘要 自闭症谱系障碍(ASD)是一种神经发育障碍，由社会缺陷定义并受到限制 以及重复的行为。这些行为与感觉处理受损和 传感器马达集成。此外，ASD通常与智力残疾(ID)和认知障碍并存 减损。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，感觉处理对认知功能和学习是至关重要的 特别是，目前尚不清楚自闭症患者的感觉处理缺陷如何有助于认知和学习。 患者的损害。我假设ASD患者的学习障碍源于感觉加工 缺陷导致对习得行为至关重要的皮质功能连接中断。我要测试一下这个想法 通过使用主要ASD遗传风险的小鼠模型，显示出触觉工具性学习障碍。 重要的是，学习障碍需要皮质兴奋性投射神经元中asd风险基因的功能。 (见初步数据)突出了皮质处理在这种表型中的重要性。此外，这些 动物对触摸的大脑皮层反应减弱。在目标1中，我将评估ASD风险基因对 通过监测小鼠接受被动感觉时的钙动力学来实现背侧皮质的感觉加工 刺激。此外，我还将操作感觉皮层中的ASD风险基因，以测试其自主控制 钙动力学和连通性。我预计ASD风险基因模型小鼠的反应将在 感觉皮层和背侧皮质下游区域的功能连接中断。在《目标2》中，我会 当小鼠执行工具性学习任务时，监测背侧皮质钙动力学，以测试这种想法 主要的ASD风险基因导致皮质功能连通性的动态改变。此外，我会决定 小鼠模型中假定的中尺度连通性缺陷在多大程度上预测学习障碍 任务。最后，我将专门操纵感觉皮质中的ASD风险基因，以测试其在 在学习过程中调节功能连接。这项提议的影响将是理解 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 介绍ASD患者认知障碍治疗方法的发展。总而言之，我是一个优秀的 由于我在ASD风险基因方面的背景，我被提名为国家研究服务奖奖学金的候选人 由伦博实验室提供的尖端系统神经科学工具的研究和培训。 总之，这里提出的培训和实验将使我加深对自闭症和 为我经营独立研究实验室的职业目标奠定了坚实的基础。

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.