Neural Mechanisms of Predictive Impairments in Autism

自闭症预测性障碍的神经机制

基本信息

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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Visual Familiarity Induced 5-Hz Oscillations and Improved Orientation and Direction Selectivities in V1.

DOI：
10.1523/jneurosci.1337-20.2021
发表时间：
2021-03-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Gao M;Lim S;Chubykin AA
通讯作者：
Chubykin AA

Impaired Adaptation and Laminar Processing of the Oddball Paradigm in the Primary Visual Cortex of Fmr1 KO Mouse.

DOI：
10.3389/fncel.2021.668230
发表时间：
2021
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Pak A;Kissinger ST;Chubykin AA
通讯作者：
Chubykin AA

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

DOI：
10.1016/j.isci.2023.107842
发表时间：
2023-10-20
期刊：
ISCIENCE
影响因子：
5.8
作者：
Cheng, Xi;Tang, Yu;Vidyadhara, D. J.;Li, Ben-Zheng;Zimmerman, Michael;Pak, Alexandr;Nareddula, Sanghamitra;Edens, Paige Alyssa;Chandra, Sreeganga S.;Chubykin, Alexander A.
通讯作者：
Chubykin, Alexander A.

A 0.43 g Wireless Battery-Less Neural Recorder With On-Chip Microelectrode Array and Integrated Flexible Antenna.

DOI：
10.1109/lmwc.2022.3167311
发表时间：
2022-06
期刊：
IEEE MICROWAVE AND WIRELESS COMPONENTS LETTERS
影响因子：
3
作者：
Shan, Hengying;Peterson, John, III;Conrad, Nathan J.;Tang, Yu;Zhu, Yuhang;Ghotbi, Shabnam;Hathorn, Sutton;Chubykin, Alexander A.;Mohammadi, Saeed
通讯作者：
Mohammadi, Saeed

Visual experience induces 4-8 Hz synchrony between V1 and higher-order visual areas.