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.

摘要 流行病学数据表明，在怀孕期间接触感染可能会引发一种改变的轨迹 胎儿大脑发育并增加后代神经发育障碍的风险，包括精神分裂症 (深圳)。母体免疫激活(MIA)的动物模型已经证明，实验激活的 母体免疫系统和随后的母体细胞因子反应诱导子代大脑的变化 以及与人类神经发育障碍相关领域的行为发展。虽然许多母亲 在怀孕期间有免疫挑战，只有这些母亲所生的孩子中的一部分会发育 神经发育障碍。这暗示了潜在的理论，即一些孩子可能天生就是 易受MIA感染。MIA恢复力和易感性的最重要因素之一可能是遗传因素， 因为几种疾病表现为遗传易感性和环境风险的相互作用。其中一个基因是 尤其令人感兴趣的是DISC1(精神分裂症中的精神分裂症-1)基因。DISC1是在苏格兰大城市中发现的 家系与SZ和SZ谱系障碍、双相情感障碍和情绪的高发病率有关 精神错乱。DISC1被发现对正常的神经发育是必要的，通过与 胚胎和成人的神经发生、突触传递、神经元增殖、皮质生成和突触 队形。DISC1-/-的动物模型已被用来描述SZ的病理生理和风险，因为它们模拟 SZ患者中常见的神经发育异常。DISC1-/-模型提供了一个机会 探索基因和环境对MIA结果的影响。MIA染毒DISC1-/-小鼠的初步研究 已经开始发现有希望的基因与环境之间的相互作用。然而，仅仅依靠鼠标模型 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SZ相关表型。此外，以前的MIA DISC1-/-研究没有检查 新生儿全脑免疫反应与子代发育的关系 细胞因子、行为和成人多巴胺D2受体水平。我们提出了一种新的大鼠模型来研究 基因与环境的交互作用在内毒素诱导的MIA和MIA大鼠特征中的作用 DISC1基因敲除。成功完成拟议的目标将开始揭示遗传易感性如何可能 塑造MIA后代的表型。