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 许多自闭症谱系障碍（ASD）的儿童表现出背纹状体的增大，大脑 基底神经节内的结构以其在运动行为和习惯的自动化中而闻名 形成。据推测，背纹状体异常有助于限制性重复行为 （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，常规的僵化和固定利益。我们的实验室有 以前证明，产前压力是已知的环境风险因素 神经发育障碍导致小鼠后代的背纹状体扩大。这些后代 还显示依赖纹状体的学习缺陷。到目前为止，背纹状体的神经生物学具有 未在总体积和中刺神经元（MSN）密度之外进行研究。 MSN，包括 大多数背纹状体形成了两种相反的途径：直接和间接。为了更好 了解纹状体发育功能障碍，纹状体的进一步分子和细胞研究 扩大是必要的。在AIM 1中，产前压力将被用作神经发育风险的模型和 纹状体增大。产前压力小鼠将根据纹状体依赖性学习行为进行评估， 为了确认产前应激的先前观察到的作用。直接与间接MSN的比率将为 使用免疫组织化学测量，揭示了纹状体增大是否由一种亚型驱动。 此外，单细胞RNA测序分析将鉴定基因和生物学途径，这些途径在 细胞亚型特异性方式扩大纹状体。在AIM 2中，测试产前纹状体的充分性 在行为缺陷上过度生长，将引入代谢型谷氨酸受体激动剂CHPG 室内室内脑中发育中的小鼠胚胎的大脑。这将特别促进细胞 外侧神经节显着性的增殖，瞬态胚胎结构，背纹状体从中。 主要出现。这些研究一起将阐明纹状体在发育过程中的过度生长 在RRB中起着至关重要的作用。这些实验的发现将有助于设计新方法 对ASD和其他相关神经发育障碍的预防和治疗治疗。