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Cellular and molecular investigations of striatal enlargement in prenatal stress model of neurodevelopmental risk

神经发育风险产前应激模型中纹状体增大的细胞和分子研究

基本信息

批准号：
10678508
负责人：
Maya Evans
金额：
$ 3.61万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678508
关键词：
Adult Children Affect Agonist Automation Basal Ganglia Behavior Behavioral Biological Brain Cell Proliferation Cells Child Corpus striatum structure Data Development Diagnosis Disease Dorsal Embryo Embryonic Structures Environmental Risk Factor Exhibits Functional disorder Future Gene Expression Genes Growth Habits Immunohistochemistry Individual Injections Investigation Laboratories Lateral Lead Learning Link Measures Mental disorders Metabotropic Glutamate Receptors Methods Modeling Molecular Motor Activity Mus Neurobiology Neurodevelopmental Disorder Neurodevelopmental Impairment Neurons Pathway interactions Pattern Play Pregnancy Prevention Process Proliferating Regulation Risk Role Scheme Stereotyped Behavior Stress Structure Symptoms Testing Therapeutic United States autism spectrum disorder autistic children behavioral outcome density design diagnostic criteria disability experimental study habit learning in utero interest learned behavior motor behavior mouse model offspring prenatal prenatal stress prevent repetitive behavior risk mitigation sample fixation single-cell RNA sequencing therapy design time interval

项目摘要

Project Abstract Many children with autism spectrum disorder (ASD) exhibit enlargement of the dorsal striatum, a brain structure within the basal ganglia that is known for its roles in automation of motor behavior and habit formation. It is postulated that abnormalities in the dorsal striatum contribute to restrictive, repetitive behavior (RRB), a diagnostic criterion for ASD and a component of other neurodevelopmental impairments encompassing repetitive motor behavior, inflexibility in routine, and fixated interests. Our laboratory has previously demonstrated that prenatal stress, which is a known environmental risk factor for neurodevelopmental disorders, leads to enlargement of the dorsal striatum in mouse offspring. These offspring also display deficits in striatal-dependent learning. So far, the neurobiology of the enlarged dorsal striatum has not been investigated beyond total volume and medium spiny neuron (MSN) density. MSNs, which comprise the majority of the dorsal striatum, form two opposing pathways: direct and indirect. In order to better understand striatal developmental dysfunction, further molecular and cellular investigations of striatal enlargement are necessary. In Aim 1, prenatal stress will be used as a model of neurodevelopmental risk and striatal enlargement. Prenatally-stressed mice will be evaluated on striatal-dependent learning behaviors, in order to confirm the previously-observed effects of prenatal stress. The ratio of direct to indirect MSNs will be measured using immunohistochemistry, revealing whether striatal enlargement is driven by one subtype. Additionally, single-cell RNA sequencing analysis will identify genes and biological pathways that are altered in the enlarged striatum in a cell subtype-specific manner. In Aim 2, to test the sufficiency of prenatal striatal overgrowth on behavioral deficits, the metabotropic glutamate receptor agonist CHPG will be introduced intracerebroventricularly to the brains of developing mouse embryos. This will specifically promote cellular proliferation in the lateral ganglionic eminence, the transient embryonic structure from which the dorsal striatum primarily arises. Together, these studies will shed light on how overgrowth of the striatum during development plays a crucial role in RRB. The findings from these experiments will aid the design of new methods of prevention and therapeutic treatment for ASD and other related neurodevelopmental disorders.

项目摘要