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

• 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
• 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

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，影响着美国大约五分之一的儿童 美国。自闭症谱系障碍 (ASD) 的特点是社交互动缺陷、重复行为和/或受限 兴趣，并且常常与智力障碍相关。尽管自闭症谱系障碍（ASD）显然是发展性的，但 诊断通常发生在 2-3 岁时，大多数人不会随着年龄的增长而不再诊断并继续 成年后患有功能障碍。患有自闭症谱系障碍 (ASD) 的成年人会经历更大的失业和社会影响 与患有其他发育障碍的同龄人相比，他们更加孤立，强烈支持治疗的需要 针对成人。一些研究报告了自闭症谱系障碍（ASD）患者症状的改善 成年期的干预，增加了成人自闭症谱系障碍大脑的可塑过程的可能性 增强优化功能。许多大脑区域都与自闭症谱系障碍有关，但其中 海马体值得注意，因为它参与社会和认知行为，并表现出持续的 终生的可塑性。神经元周围网 (PNN) 是细胞外基质结构，可抑制 可塑性并与神经精神疾病有关。研究发现突变的证据 与 ASD 细胞外基质相关的基因，但之前的工作尚未研究是否 PNN 会导致社交和认知功能障碍。研究表明 PNN 和正齿牙 同源盒 2 (OTX2) 是一种对 PNN 维持很重要的转录因子，在 ASD 小鼠中含量过多 在海马 CA2 和 CA3 区域，这些区域对于社交和情境/空间处理很重要。 没有研究调查是否可以使海马 PNN 和 OTX2 正常化的干预措施 减轻与 ASD 相关的问题行为。先前的研究表明，自闭症谱系障碍（ASD）小鼠 海马体出生后神经发生减少，并且由于成年产生的神经元有助于 社交行为以及学习和记忆，成人神经发生减少可能会加剧自闭症谱系障碍 症状。海马体中新神经元的许多目标位点都被 PNN 包围，并且从那时起 众所周知，PNN 会抑制可塑性，它们在 ASD 中的过度生产可能会妨碍最佳连接 成型。该提案将解决我们对异常 PNN 及其如何产生影响的理解上的差距。 与成年神经元的连接导致自闭症谱系障碍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、共聚焦和电子显微镜免疫标记、药物和 神经发生的体验刺激和行为分析以探索干预措施的功效 通过标准化 PNN、减少 OTX2 和优化之间的连接来减轻 ASD 症状 新神经元和 PNN+ 目标。拟议的工作将增进我们对结构如何 海马体的可塑性可能会增强，从而有助于改善社交和认知能力 成人自闭症谱系障碍 (ASD) 患者的功能障碍。