A novel neural circuit analysis paradigm to model autism in mice

一种新颖的神经回路分析范例来模拟小鼠自闭症

基本信息

批准号：
8747757
负责人：
YONG-HUI JIANG
金额：
$ 19.67万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747757
关键词：
Address Animals Area Autistic Disorder Behavior Behavioral Biological Markers Biological Neural Networks Brain Brain region Collection Communication Deep Brain Stimulation Defect Development Disease Disease model Distal Electrodes Electroencephalography Environmental Risk Factor Exhibits Exons Experimental Designs Exploratory/Developmental Grant Face Frequencies Functional Magnetic Resonance Imaging Functional disorder Generations Genes Genetic Goals Grooming Heterogeneity Hippocampus (Brain)Human Knowledge Lead Learning Link Magnetoencephalography Methods Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Pacemakers Pathogenesis Pathway interactions Pharmaceutical Preparations Physiology Positron-Emission Tomography Prefrontal Cortex Process Research Research Personnel Rodent Series Slice Social Behavior Social Interaction Synapses Techniques Time Transcranial magnetic stimulation Validation autism spectrum disorder autistic behaviour base behavioral impairment clinical Diagnosis effective therapy electrical measurement endophenotype gene function high reward high risk in vivo insight millisecond mouse model neural circuit neurophysiology neuropsychiatry novel public health relevance relating to nervous system repaired research study skills social stem trait

项目摘要

A Novel Neural Circuit Analysis Paradigm to Model Autism in Mice The circuit defects underlying the behavioral impairments of autism spectrum disorders (ASD) remains poorly understood. This knowledge is critical for development of effective treatments. The considerable molecular heterogeneity in human ASD and the apparent limitations in human studies renders mutant mice with targeted mutations equivalent to humans a unique opportunity because it allows manipulation at both molecular and circuit levels. There is an increasing list of ASD models with both "construct" (molecular defect mimics human ASD) and "face" (behavioral impairments equivalent to core feature of human ASD) validity. The current analytic paradigm of modeling human ASD in mutant mice focuses on analyzing synaptic development and function using slice physiology and behavior analysis. These studies have produced evidence supporting a general conclusion of synaptic dysfunction in ASD models. However, these findings offer little insight into the circuit mechanism underlying behavioral impairments because the findings from studying the synapses in select brain regions are frequently variable and inconsistent among different studies. The fundamental challenge of ASD research lies within the complexity of understanding how alterations in gene function disrupt large scale brain networks responsible for normal functional process underlying autistic behaviors. For these reasons, the field of modeling human ASD in genetically modified mutant mice demands a new analytic paradigm to dissect the dysfunction at circuit or network levels. We have developed a novel multi-unit in vivo recoding technique that can acquire neural activity from as many as 11 brain regions in free moving animals simultaneously. This novel technique offers a feasibility to detect dysfunctional neural circuit and network. We have also produced and characterized unique Shank2 exon 24 (Shank3e24) and Shank3 exon 4-22 (Shank3e4- 22) deletion mutant mice that have strong construct and face validity for human ASD. These mutant mice provide unique opportunities to develop a novel analytic paradigm for dissecting circuit dysfunction. The long term goal of this project is to define dysfunctional circuit underlying ASD behaviors using ASD mouse models. The central hypothesis is dysfunction synchrony across distinct relevant neural circuits will be observed in Shank3e4-22 and Shank2e24 mutant mice. The specific objective is to identify the dysfunctional neural circuits underlying social deficits and repetitive behaviors in these mutant mice using a novel in vivo multiple-unit recording technique pioneered by our team. These experiments will lead to the identification of electrophysiological biomarkers of endophenotypes that will aid in the validation of novel molecular targets for novel neuropsychiatric drugs, enhance the targeting of current neuromodulatory therapies for use in ASD and facilitate the development of closed loop neuromodulatory "pacemakers" which directly repair the dysfunctional brain circuits underlying the behavioral manifestations in ASD. These findings will address a significant gap in our knowledge and provide evidence to support a paradigm shift in modeling human ASD using mutant mice.

一种新的神经回路分析范式来模拟小鼠自闭症自闭症谱系障碍 (ASD) 行为障碍背后的回路缺陷仍然很差明白了。这些知识对于开发有效的治疗方法至关重要。相当大的分子人类 ASD 的异质性和人类研究的明显局限性使得突变小鼠具有针对性相当于人类的突变是一个独特的机会，因为它允许在分子和电路电平。越来越多的 ASD 模型同时具有“结构”（分子缺陷模仿人类） ASD）和“面子”（相当于人类 ASD 核心特征的行为障碍）有效性。目前的在突变小鼠中模拟人类 ASD 的分析范式侧重于分析突触发育和使用切片生理学和行为分析的功能。这些研究提供了证据支持 ASD 模型中突触功能障碍的一般结论。然而，这些发现并没有让我们深入了解行为障碍背后的电路机制，因为研究突触的结果在不同的研究中，选定的大脑区域经常变化且不一致。基本的自闭症谱系障碍研究的挑战在于理解基因功能的改变如何破坏的复杂性负责自闭症行为背后的正常功能过程的大规模大脑网络。对于这些由于这些原因，在转基因突变小鼠中模拟人类自闭症谱系障碍需要一种新的分析方法剖析电路或网络级别功能障碍的范例。我们开发了一种新型体内多单元重新编码技术可以获取自由活动动物多达 11 个大脑区域的神经活动同时地。这项新技术提供了检测功能失调的神经回路和网络的可行性。我们还产生并表征了独特的 Shank2 外显子 24 (Shank3e24) 和 Shank3 外显子 4-22 (Shank3e4- 22) 缺失突变小鼠，具有强大的结构并且对人类自闭症谱系障碍有效。这些突变小鼠为开发一种用于剖析电路功能障碍的新颖分析范式提供了独特的机会。长的该项目的长期目标是使用 ASD 小鼠模型定义 ASD 行为背后的功能失调电路。中心假设是不同相关神经回路之间的同步功能障碍将在 Shank3e4-22 和 Shank2e24 突变小鼠。具体目标是识别功能失调的神经回路使用新型体内多单元研究这些突变小鼠潜在的社交缺陷和重复行为我们团队首创的录音技术。这些实验将导致鉴定内表型的电生理生物标志物将有助于验证新的分子靶标新型神经精神药物，增强当前神经调节疗法用于自闭症谱系障碍（ASD）和促进闭环神经调节“起搏器”的发展，直接修复功能失调的自闭症谱系障碍行为表现背后的大脑回路。这些发现将解决以下方面的重大差距：我们的知识并提供证据支持使用突变小鼠模拟人类自闭症谱系障碍的范式转变。