Neural Mechanisms of Predictive Impairments in Autism

自闭症预测性障碍的神经机制

• 批准号: 10660345
• 负责人: Alexander Chubykin
• 金额: $ 48.97万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660345
• 关键词: ASD patient; Anatomy; Anterior; Area; Behavior; Behavioral; Brain; Code; Computer Models; Cortical Cell Layer; Cues; Data; Decision Making; Detection; Development; Discrimination; Electrophysiology (science); Elements; Event; FMR1; FMRP; Familiarity; Fragile X Syndrome; Frequencies; Funding; Future; Generations; Goals; Grant; Human; Impairment; In Vitro; Intellectual functioning disability; Interneurons; Knockout Mice; Learning; Learning Disabilities; Life; Link; Maps; Measures; Modeling; Mus; Neocortex; Neurons; Outcome; Patients; Pattern; Process; Publications; Reporting; Research; Role; Sensory; Short-Term Memory; Slice; Social Interaction; Stimulus; Synapses; Synaptic plasticity; System; Therapeutic; Time; Visual; Visual Perception; area striata; autism spectrum disorder; awake; behavior prediction; cell type; cingulate cortex; data modeling; diagnostic criteria; expectation; experience; extracellular; feasibility research; in vivo; individuals with autism spectrum disorder; information processing; mouse model; neocortical; neural; neural circuit; neuromechanism; novel; optogenetics; personalized medicine; pharmacologic; restoration; selective expression; sensory stimulus; social communication; synaptogenesis; therapeutic target; visual learning; ASD patient; Anatomy; Anterior; Area; Behavior; Behavioral; Brain; Code; Computer Models; Cortical Cell Layer; Cues; Data; Decision Making; Detection; Development; Discrimination; Electrophysiology (science); Elements; Event; FMR1; FMRP; Familiarity; Fragile X Syndrome; Frequencies; Funding; Future; Generations; Goals; Grant; Human; Impairment; In Vitro; Intellectual functioning disability; Interneurons; Knockout Mice; Learning; Learning Disabilities; Life; Link; Maps; Measures; Modeling; Mus; Neocortex; Neurons; Outcome; Patients; Pattern; Process; Publications; Reporting; Research; Role; Sensory; Short-Term Memory; Slice; Social Interaction; Stimulus; Synapses; Synaptic plasticity; System; Therapeutic; Time; Visual; Visual Perception; area striata; autism spectrum disorder; awake; behavior prediction; cell type; cingulate cortex; data modeling; diagnostic criteria; expectation; experience; extracellular; feasibility research; in vivo; individuals with autism spectrum disorder; information processing; mouse model; neocortical; neural; neural circuit; neuromechanism; novel; optogenetics; personalized medicine; pharmacologic; restoration; selective expression; sensory stimulus; social communication; synaptogenesis; therapeutic target; visual learning

Autism spectrum disorders (ASDs) are characterized by altered sensory processing and intellectual disability. Atypical sensory processing has been recognized as an important diagnostic criterion for autism and is predictive of social communication deficits later in life. ASDs are also associated with impaired structural and functional connectivity within and between neocortical areas. However, how impaired neural connectivity, which is present in ASDs, leads to impaired sensory processing and learning is not understood. Recently, we have discovered new visual familiarity-evoked theta oscillations in the primary visual cortex (V1). In Fmr1 KO mice, a mouse model of Fragile X syndrome, these oscillations are weaker, shorter, and frequency shifted. Furthermore, we have shown a similar emergence of visually cued theta oscillations in the anterior cingulate cortex (ACC), an area connected to V1 and involved in social interaction, decision making and error detection. We have also started mapping the neural circuit underlying these oscillations. Our prior studies suggest that these familiarity-evoked theta oscillations and the underlying changes in the neural circuit connectivity may be the cause of impairments in visual learning and perception. Our preliminary data also suggest that Fmr1 KO mice demonstrate impaired theta oscillations in a visual discrimination task. We have developed a computational model to reproduce theta oscillations in the cortex. This proposal builds on foundational advances by dissecting the mechanisms of theta oscillations in WT and Fmr1 KO mice. Using an integrated approach combining mapping of neuronal connectivity in brain slices, in vivo extracellular recordings, and behavior, we will: 1) map the circuitry necessary to form a theta oscillator in V1 and identify altered connectivity patterns within V1 and between V1 and ACC in Fmr1 KO mice, 2) examine how the strength of theta oscillations in V1 and ACC correlates with behavior in WT and Fmr1 KO mice following learning, and 3) rescue theta oscillations by restoring FMRP expression selectively only in the specific neuronal groups in Fmr1 KO mice guided by the computational model. Based on our prior studies, preliminary data, and computational model, we expect to see familiarity-evoked theta oscillations correlate with successful behavior in a visual discrimination task. We also expect to identify the critical parts of the neural circuit required for the generation of theta oscillations and its impairment in Fmr1 KO mice. Results from this proposal will help inform the development of targeted neural circuit-based behavioral and pharmacological therapeutics to enable personalized medicine for individuals with ASDs.

自闭症谱系障碍（ASD）的特征是感觉处理的改变和 智力残疾。非典型感觉处理被认为是重要的诊断 自闭症的标准，可以预测生活中以后的社会交流缺陷。 ASD也是 与新皮层内和之间的结构和功能连通性受损相关 区域。但是，ASD中存在的神经连通性损害如何导致受损 感官处理和学习尚不理解。最近，我们发现了新的视觉 熟悉度引起的theta振荡在主要视觉皮层（V1）中。在FMR1 KO小鼠中，鼠标 脆弱的X综合征模型，这些振荡较弱，较短和频率变化。 此外，我们已经显示出前方视觉提示的theta振荡的出现 扣带皮层（ACC），该区域与V1连接并参与社会互动，决定 进行和错误检测。我们还开始绘制这些基础的神经回路 振荡。我们先前的研究表明，这些熟悉性引起的theta振荡和 神经电路连通性的基本变化可能是视觉障碍的原因 学习和感知。我们的初步数据还表明FMR1 KO小鼠证明了 在视觉歧视任务中，theta振荡受损。我们已经开发了一个计算 在皮质中重现theta振荡的模型。该提案以基本进步为基础 通过解剖WT和FMR1 KO小鼠中theta振荡的机制。使用集成 结合脑切片中神经元连通性的映射，体内细胞外 录音和行为，我们将：1）绘制在V1中形成theta振荡器所需的电路 并确定V1内以及V1和ACC之间的连通性模式的改变，fMR1 KO小鼠， 2）检查V1和ACC中theta振荡的强度与WT中的行为相关 学习后的FMR1 KO小鼠，以及3）通过恢复FMRP来挽救theta振荡 仅在FMR1 KO小鼠的特定神经元组中有选择地表达。 计算模型。根据我们先前的研究，初步数据和计算模型，我们 期望看到熟悉性引起的theta振荡与视觉中的成功行为相关 歧视任务。我们还期望确定神经回路的关键部分 theta振荡的产生及其在FMR1 KO小鼠中的损害。该提议的结果 将有助于告知有针对性的基于神经电路的行为和药理的发展 治疗方法可以为患有ASD的患者提供个性化医学。