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，其定义为社交缺陷和限制性发育障碍。 重复的行为。这些行为与受损的感觉处理有关， 感觉运动整合此外，ASD通常与智力残疾（ID）和认知障碍共病。 损伤这对于与几个主要ASD风险基因之一相关的ASD诊断尤其如此。 虽然已经确定感觉处理对于一般认知功能和学习至关重要， 特别是，尚不清楚ASD中感觉处理的缺陷如何有助于认知和学习 患者的损伤。我假设ASD患者的学习障碍源于感觉处理 导致对学习行为至关重要的皮质功能连接中断的缺陷。我将测试这个想法 通过使用一个有ASD遗传风险的小鼠模型，该模型显示出触觉工具性学习障碍。 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 (see初步数据），突出了皮层处理在这种表型中的重要性。另外这些 动物对触摸的皮层反应减弱。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背侧皮层中的钙动力学的感觉处理 刺激.此外，我还将操纵感觉皮层中的ASD风险基因，以测试其对自闭症的自主控制。 钙动力学和连通性。我预计ASD风险基因模型小鼠对自闭症的反应会降低， 感觉皮层和中断的功能连接到下游区域的背侧皮层。在目标2中，我将 监测背皮层钙动力学，因为小鼠执行工具学习任务，以测试的想法， 主要ASD风险基因导致皮质功能连接的动力学改变。此外，我将决定 小鼠模型中假定的中尺度连通性缺陷在多大程度上预测了 任务最后，我将专门操纵感觉皮层中的ASD风险基因，以测试其在自闭症中的自主作用。 在学习过程中调节功能连接。这项建议的影响将是了解 与主要ASD风险基因相关的学习受损的神经生物学基础，这可能有助于 为ASD患者认知缺陷的治疗提供信息。总之，我是一个优秀的 由于我在ASD风险基因方面的背景，我是国家研究服务奖奖学金的候选人 Rumbaugh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能够进一步了解ASD， 为我的职业目标--经营一个独立的研究实验室--打下了坚实的基础。

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.