Perineuronal nets, hippocampal plasticity and autism spectrum disorder

神经周围网、海马可塑性和自闭症谱系障碍

基本信息

批准号：
10390327
负责人：
Elizabeth Gould
金额：
$ 40.11万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390327
关键词：
3 year old ASD patient Address Adult Affect Area Behavior Behavioral Brain Brain Diseases Brain region Cells Child Cognition Cognitive Cognitive deficits Confocal Microscopy Dendrites Development Diagnosis Disease model Electron Microscopy Employment Etiology Exhibits Extracellular Matrix Fragile X Syndrome Functional disorder Genes Genetic Models Goals Hippocampus (Brain)Homeobox Impaired cognition Impairment Inbreeding Intellectual functioning disability Interneurons Intervention Label Learning Life Link Maintenance Mediating Memory Molecular Mus Mutate Mutation Neurodevelopmental Disorder Neurons Persons Pharmaceutical Preparations Process Production Quality of life Reporting Research Residual state Rodent Services Site Social Behavior Social Interaction Social isolation Structure Symptoms Synaptic plasticity Syndrome Therapeutic Therapeutic Intervention Transgenic Organisms Treatment Efficacy Unemployment Visual Work adult neurogenesis adult with autism spectrum disorder autism spectrum disorder density dentate gyrus developmental disease experience experimental study genome wide association study granule cell hippocampal pyramidal neuron improved improved functioning interest mouse model neurogenesis neuropsychiatric disorder peer postnatal prenatal prevent repetitive behavior restoration restraint social social deficits statistics targeted treatment therapy design transcription factor valproate

项目摘要

Project Abstract Autism spectrum disorder (ASD) is a heterogeneous condition affecting approximately 1 in 59 children in the US. ASD is characterized by deficits in social interactions, repetitive behaviors and/or restricted interests, and is often associated with intellectual disability. Although ASD is clearly developmental, with diagnoses typically occurring by 2-3 years of age, most people do not outgrow the diagnosis and continue to suffer with dysfunction in adulthood. Adults with ASD experience greater unemployment and social isolation than their peers with other developmental disorders, strongly supporting the need for therapies targeted to adults. A few studies have reported improvements in symptoms of ASD patients with interventions in adulthood, raising the possibility that plastic processes in the adult ASD brain may be enhanced to optimize function. Many brain regions have been implicated in ASD but among them the hippocampus is notable in that it is involved in both social and cognitive behavior and displays ongoing plasticity throughout life. Perineuronal nets (PNNs) are extracellular matrix structures that dampen plasticity and have been linked to neuropsychiatric disease. Studies have found evidence for mutations in genes associated with the extracellular matrix in ASD but previous work has not investigated whether PNNs contribute to social and cognitive dysfunction. Research indicates that PNNs and orthodenticle homeobox 2 (OTX2), a transcription factor important for PNN maintenance, are excessive in ASD mice in the hippocampal CA2 and CA3 regions, areas important for social and contextual/spatial processing. No studies have investigated whether interventions that normalize PNNs and OTX2 in the hippocampus mitigate problematic behaviors associated with ASD. Previous work suggests that ASD mice have reduced postnatal neurogenesis in the hippocampus and since adult-generated neurons contribute to social behavior as well as learning and memory, diminished adult neurogenesis may exacerbate ASD symptoms. Many target sites of new neurons in the hippocampus are surrounded by PNNs and since PNNs are known to inhibit plasticity, their over production in ASD may prevent optimal connections from forming. This proposal will address gaps in our understanding about how aberrant PNNs and their connections with adult-generated neurons contribute to behavioral dysfunction in ASD mice. The experiments will use transgenic and inbred ASD mouse models, manipulations of PNNs and OTX2, retroviral labeling of new neurons, immunolabeling with confocal and electron microscopy, drug and experiential stimulation of neurogenesis and behavioral analyses to explore the efficacy of interventions to mitigate ASD symptoms by normalizing PNNs, reducing OTX2 and optimizing connections between new neurons and PNN+ targets. The proposed work will advance our understanding of how structural plasticity in the hippocampus may be enhanced in the service of improving social and cognitive dysfunction in adults with ASD.

项目摘要自闭症谱系障碍（ASD）是一种异质疾病，影响了59名儿童中约1个美国。 ASD的特征是社交互动，重复行为和/或受限制的缺陷利益，通常与智力残疾有关。尽管ASD显然是发展的，但诊断通常在2-3岁以下，大多数人不会超越诊断并继续成年后患有功能障碍。 ASD的成年人经历更大的失业和社会孤立比其他发育障碍的同龄人，强烈支持对治疗的需求针对成年人。一些研究报道了ASD患者的症状改善成年中的干预措施增加了成人ASD大脑中的塑料过程的可能性增强以优化功能。许多大脑区域都与ASD有关，但其中海马在社会和认知行为中都参与了海马，并显示一生的可塑性。会内神经元网（PNN）是抑制的细胞外基质结构可塑性，与神经精神病有关。研究发现了突变的证据在与ASD中的细胞外基质相关的基因中，但以前的工作尚未研究 PNN会导致社会和认知功能障碍。研究表明PNN和正畸形 ASD小鼠的转录因子（OTX2）是PNN维护重要的转录因子（OTX2）在海马CA2和CA3区域中，对社会和背景/空间处理很重要的区域。尚无研究研究海马中PNN和OTX2的干预措施是否是否减轻与ASD相关的有问题行为。以前的工作表明ASD老鼠有降低海马的产后神经发生，并且由于成年神经元有助于社会行为以及学习和记忆，成人神经发生的减少可能加剧ASD 症状。海马中的许多新神经元的目标部位都被PNN包围，并且已知PNN可以抑制可塑性，它们在ASD中的过度生产可能会阻止最佳连接成型。该建议将解决我们对异常PNN及其如何的理解的差距与成人产生的神经元的联系导致ASD小鼠的行为功能障碍。这实验将使用转基因和近交ASD小鼠模型，PNN和OTX2的操作，新神经元的逆转录病毒标记，与共聚焦和电子显微镜的免疫标记，药物和经验刺激神经发生和行为分析以探索干预措施的功效通过标准化PNN，减少OTX2并优化之间的连接来减轻ASD症状新的神经元和PNN+靶标。拟议的工作将提高我们对结构的理解海马中的可塑性可能会增强，以改善社交和认知 ASD成人的功能障碍。