Influence of DISC1 genetics on brain and behavioral development of offspring exposed to Maternal immune activation

DISC1 遗传学对暴露于母体免疫激活的后代大脑和行为发育的影响

• 批准号: 10607339
• 负责人: Simone Grant
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607339
• 关键词: Adult; Affect; Animal Model; Animals; Anxiety; Area; Attention; Bacterial Infections; Behavior; Behavioral; Biological Models; Bipolar Disorder; Blood specimen; Brain; Candidate Disease Gene; Child; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; DISC1 gene; DRD2 gene; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Embryo; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Etiology; Exposure to; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Hour; Human; Immune; Immune response; Immune system; Incidence; Infection; Inflammatory; Interleukin-6; Knock-out; Life; Link; Mental Depression; Modeling; Mood Disorders; Mothers; Mus; Neonatal; Neurodevelopmental Disorder; Neurons; Outcome; Outcome Study; Patients; Phenotype; Predisposition; Pregnancy; Process; Proliferating; Rattus; Risk; Running; Schizophrenia; Severities; Shapes; Social Behavior; Symptoms; Synaptic Transmission; Synaptic plasticity; TNF gene; Testing; Tissues; Ultrasonics; Virus Diseases; adult neurogenesis; behavior test; behavioral phenotyping; brain tissue; caudate nucleus; comparison control; cytokine; dopamine system; epidemiologic data; fetal; gene environment interaction; genetic pedigree; immune activation; interest; maternal immune system; migration; mouse model; neonatal brain; neurite growth; neurodevelopment; neurogenesis; novel; offspring; pre-clinical; prenatal; pup; resilience; resilience factor; response; schizophrenia spectrum disorder; social; stressor; symptomatology; synaptic pruning; synaptogenesis; theories; training opportunity; vocalization

Abstract Epidemiological data suggest that exposure to infection during pregnancy may initiate an altered trajectory of fetal brain development and increases risk of offspring neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) have demonstrated that experimental activation of the maternal immune system and the subsequent maternal cytokine response induces changes in offspring brain and behavioral development in domains relevant to human neurodevelopmental disorders. While many mothers have immune challenges during pregnancy, only a subset of the children born to those mothers develop neurodevelopmental disorders. This hints at the potential theory that some children may be inherently susceptible to MIA. One of the most important factors for resilience and susceptibility in MIA may be genetics, as several disorders manifest as an interaction of genetic susceptibility and environmental risk. One gene of particular interest is the DISC1 (Disrupted-in-schizophrenia-1) gene. DISC1 was discovered in large Scottish pedigree and is linked to a higher incidence of SZ and SZ spectrum disorders, bipolar disorder, and mood disorders. DISC1 has been found to be necessary for proper neurodevelopment, through associations with embryonic and adult neurogenesis, synaptic transmission, neuronal proliferation, corticogenesis, and synapse formation. Animal models of DISC1-/- have been used to characterize SZ pathophysiology and risk, as they mimic the aberrant neurodevelopment that is often seen in SZ patients. The DISC1-/- model provides an opportunity to explore gene by environment effects on MIA outcomes. Preliminary studies of DISC1-/- mice exposed to MIA have begun to uncover promising gene by environment interactions. However, relying solely on mouse models limits our ability to evaluate complex social and cognitive behaviors, two areas which are critical for understanding SZ-related phenotypes. In addition, previous MIA DISC1-/- studies have not examined the relationship of the dam’s immune response to the development of the offspring through neonatal whole brain cytokines, behavior, and adult dopamine D2 receptor levels. We propose a novel rat model to investigate the interactions between gene and environment in characterizing rats exposed to both LPS-induced MIA and the DISC1 knockout. Successful completion of the proposed aims will begin uncover how genetic susceptibility may shape MIA offspring phenotypes.

抽象的 流行病学数据表明，怀孕期间接触感染可能会引发改变的轨迹 胎儿脑发育并增加后代神经发育障碍的风险，包括精神分裂症 （SZ）。母体免疫激活（MIA）的动物模型表明，实验激活 母体免疫系统和随后的基质细胞因子反应诱导后代大脑的变化 和与人类神经发育障碍有关的领域的行为发展。而许多母亲 怀孕期间面临免疫挑战，只有那些母亲出生的子集 神经发育障碍。这暗示了潜在的理论，有些孩子可能是天生的 容易受到MIA的影响。 MIA的弹性和敏感性最重要的因素之一可能是遗传学， 由于几种疾病表现为遗传易感性和环境风险的相互作用。一个基因 椎间盘1（中断中断的基因）基因特别感兴趣。在大型苏格兰人中发现了Disc1 谱系，与更高的SZ和SZ光谱障碍，躁郁症和情绪有关 疾病。通过与 胚胎和成人神经发生，突触传播，神经元增殖，皮层生成和突触 形成。椎间盘的动物模型已被用来表征SZ的病理生理学和风险，因为它们模仿它们 在SZ患者中经常看到的异常神经发育。 DISC1 - / - 模型提供了一个机会 通过环境对MIA结果的影响探索基因。暴露于MIA的Disc1 - / - 小鼠的初步研究 已经开始通过环境相互作用来揭示承诺基因。但是，仅依靠鼠标模型 限制了我们评估复杂的社会和认知行为的能力，这两个领域对 了解与SZ相关的表型。此外，以前的MIA Disc1 - / - 研究尚未检查 大坝对通过新生儿整个大脑的后代发展的免疫反应的关系 细胞因子，行为和成年多巴胺D2受体水平。我们提出了一个新型的大鼠模型来研究 基因与环境之间的相互作用在表征暴露于LPS诱导的MIA和的大鼠方面 Disc1淘汰赛。成功完成提议的目标将开始揭示遗传易感性如何 塑造MIA后代表型。