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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：
9981032
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/9981032
关键词：
3 year old 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 Patients 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 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