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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：
10610384
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610384
关键词：
3 year old ASD patient Address Adult Affect Area Axon 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 Experimental Models Extracellular Matrix Fragile X Syndrome Functional disorder Genes Genetic Models Goals Hippocampus Homeobox Human 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 Cortex Work adult neurogenesis adult with autism spectrum disorder autism spectrum disorder density dentate gyrus developmental disease experience experimental study functional improvement genome wide association study granule cell hippocampal pyramidal neuron improved interest mouse model neurogenesis neuropsychiatric disorder peer postnatal prenatal prevent repetitive behavior restoration restraint social social deficits social relationships 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)是一种异质性疾病，大约每59名儿童中就有1名受到影响美国。ASD的特征是社交功能障碍、重复行为和/或受限兴趣，往往与智力残疾联系在一起。尽管ASD明显是发育性的，诊断通常发生在2-3岁，大多数人不会长大后放弃诊断并继续在成年后患有功能障碍。患有自闭症的成年人失业率更高，社交能力更强与患有其他发育障碍的同龄人相比，与世隔绝，强烈支持治疗的必要性目标人群为成年人。少数研究报告了ASD患者症状的改善。成年期的干预，增加了成人ASD大脑中的可塑性过程可能是增强以优化功能。许多大脑区域都与ASD有关，但其中值得注意的是，海马体参与了社会和认知行为，并显示出持续的生命中的可塑性。周围神经网络(PNN)是一种细胞外基质结构，可抑制可塑性，并与神经精神疾病有关。研究发现了突变的证据在ASD中与细胞外基质相关的基因中，但以前的工作还没有研究 PNNS会导致社交和认知功能障碍。研究表明，PNNS和正畸同源框2(OTX2)是一种对PNN维持至关重要的转录因子，在ASD小鼠中过度表达在海马区的CA2和CA3区，对社会和背景/空间加工很重要的区域。没有研究调查是否干预使PNNS和OTX2在海马区正常化缓解与ASD相关的问题行为。先前的研究表明，ASD小鼠有出生后海马区神经发生减少，因为成体产生的神经元对社会行为以及学习和记忆，成人神经发生减少可能会加重ASD 症状。海马区新神经元的许多靶点被PNNS包围，因为已知PNN抑制可塑性，它们在ASD中的过度产生可能会阻止最佳连接正在形成。这项提议将解决我们对异常的PNN和他们的与成人产生的神经元的联系有助于ASD小鼠的行为功能障碍。这个实验将使用转基因和近交系ASD小鼠模型，操作PNNS和OTX2，新神经元的逆转录病毒标记，共聚焦免疫标记和电子显微镜，药物和神经发生的体验式刺激和行为分析探讨干预效果通过正常化PNNS、减少OTX2和优化新的神经元和PNN+靶点。拟议的工作将促进我们对结构如何在改善社会和认知方面，海马区的可塑性可能会增强成人ASD患者的功能障碍。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice.

DOI：
10.1038/s41467-023-37248-8
发表时间：
2023-03-29
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Cope, Elise C.;Wang, Samantha H.;Waters, Renee C.;Gore, Isha R.;Vasquez, Betsy;Laham, Blake J.;Gould, Elizabeth
通讯作者：
Gould, Elizabeth

Perineuronal Nets in the Dorsomedial Striatum Contribute to Behavioral Dysfunction in Mouse Models of Excessive Repetitive Behavior.