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

• 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
• 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

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 许多患有自闭症谱系障碍（ASD）的儿童表现出背侧纹状体（一种大脑）的扩大 基底神经节内的结构，以其在运动行为和习惯的自动化中的作用而闻名 阵据推测，背侧纹状体的异常有助于限制，重复行为 (RRB)，ASD的诊断标准和其他神经发育障碍的组成部分 包括重复的运动行为，日常生活中的可持续性，以及固定的兴趣。本实验室 以前证明，产前压力，这是一个已知的环境风险因素， 神经发育障碍导致小鼠后代背侧纹状体增大。这些后代 还表现出依赖于纹状体的学习缺陷。到目前为止，扩大的背侧纹状体的神经生物学 除了总体积和中等多刺神经元（MSN）密度外，没有进行研究。MSN，包括 背侧纹状体的大部分形成两个相反的通路：直接通路和间接通路。为了更好 了解纹状体发育功能障碍，进一步的纹状体发育的分子和细胞研究， 扩大是必要的。在目标1中，产前压力将被用作神经发育风险的模型， 纹状体增大将评估产前应激小鼠的纹状体依赖性学习行为， 以证实先前观察到的产前压力的影响。直接MSN与间接MSN的比例为 用免疫组织化学方法测量，揭示纹状体增大是否由一种亚型驱动。 此外，单细胞RNA测序分析将识别在细胞内改变的基因和生物学途径。 以细胞亚型特异的方式扩大纹状体。目的2：检测产前纹状体发育的充分性， 过度生长的行为缺陷，代谢型谷氨酸受体激动剂CHPG将被引入 脑室内注射到发育中的小鼠胚胎的大脑中。这将特别促进细胞 侧神经节隆起的增殖，背侧纹状体的短暂胚胎结构 首先出现。总之，这些研究将阐明纹状体在发育过程中的过度生长 在RRB中起着关键作用。这些实验的结果将有助于设计新的方法， 预防和治疗ASD和其他相关神经发育障碍。