Understanding cellular and molecular legacies of paternal stress

了解父亲压力的细胞和分子遗产

• 批准号: 10674637
• 负责人: Brian George DIAS
• 金额: $ 71.5万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674637
• 关键词: Adolescence; Adult; Affect; Animals; Astrocytes; Attention; Behavior; Biochemistry; Biology; Brain; Cells; Chemicals; Child; Communication; Complex; Conceptions; Data; Development; Developmental Biology; Dimensions; Embryo; Epigenetic Process; Event; Exposure to; Extinction (Psychology); Famines; Fathers; Generations; Genes; Glucocorticoid Receptor; Goals; Holocaust; Human; Immunoprecipitation; Impairment; Injections; Investigation; Knock-out; Knowledge; Learning; Light; Longevity; Measures; Mediator of activation protein; Memory; Mental Health; Mental disorders; Messenger RNA; MicroRNAs; Mission; Molecular; Molecular Genetics; Motion; Mus; Mutation; National Institute of Mental Health; Neurobiology; Neurons; Parents; Pathway interactions; Play; Post-Traumatic Stress Disorders; Poverty; Prefrontal Cortex; Pregnancy; Prevention; Process; Public Health; RNA; Receptor Gene; Regulation; Research; RiboTag; Risk; Rodent; Role; Signal Transduction; Stimulus; Stress; Synapses; Testing; Training; Translating; Translations; Trauma; Work; antenatal; anthropogenesis; base; caregiving; cell growth; cell type; experience; high risk; in vivo; insight; intergenerational; learning extinction; male; nervous system development; neurobiological mechanism; offspring; overexpression; receptor expression; receptor function; response; sperm cell; therapeutic target; translational impact; zygote

PROJECT SUMMARY: Famines, the Holocaust and other natural and anthropogenic events are providing evidence that the effects of trauma and stress extend beyond the ancestral generation and affect mental health in offspring. Remedying parental behavior that is perturbed by stress and mitigating stress during pregnancy have received attention for their utility in halting such legacies of stress. In contrast, less is known about how to halt legacies of paternal stress that occurred prior to conception of the affected offspring. To fill this gap in knowledge, we must first understand how stress-induced alterations in paternal sperm perturb neurobiology and derail mental health. With this intent, our goal is to determine how cell-type specific offspring neurobiology is impacted by stress-induced alterations in sperm RNA that have emerged as one mechanism via which paternal lineages bequeath legacies of stress to offspring. To achieve this goal, we rely on our experience studying legacies of paternal stress, learning and memory in mice and build on unpublished data demonstrating that injections of RNA from sperm of male mice exposed to stress into single cell zygotes resulted in deficits in extinction learning in adulthood. To begin our investigation into the neurobiological mechanisms that might underlie these deficits in extinction learning being set into motion by RNA in sperm exposed to stress, we propose a focus on glucocorticoid receptors (GRs) in the infra-limbic prefrontal cortex (IL-PFC), lactate-based activity of neurons in the IL-PFC, and development of the IL-PFC. Our focus is shaped by the following background. First, the IL-PFC is important for extinction learning. Second, epigenetic-based regulation of the GR gene has received the most attention in studies that have investigated intergenerational legacies of stress arising from abusive care-giving and gestational stress, in both humans and rodents. Third, lactate-based signaling between astrocytes and neurons is an important mode of communication between these cell types, plays a role in learning and memory, and is perturbed in offspring by ante-natal stress. Fourth, altered development of the PFC in humans and rodents as a consequence of impoverished caregiving and gestational stress derails behavior in offspring during adulthood. Motivated by this background, we hypothesize that deficits in extinction learning that are set into motion by RNA contained in sperm of mice exposed to stress result in part, from altered GR availability in the IL-PFC, disrupted lactate-based activity of IL-PFC neurons, and an immaturity of the adult IL-PFC. To test this hypothesis, we will use biochemistry, molecular genetics, developmental biology and in vivo manipulation of neuronal activity with a focus on the IL- PFC of animals generated from embryos into which RNA from sperm of male mice exposed to stress had been injected. Via cell- and region-specific investigations, our work will provide new insights into how stress- induced alterations in sperm RNA are translated into neurobiological legacies and may have translational impact by identifying biology that could be therapeutically targeted to lighten the burden of such legacies.

项目摘要：饥荒，大屠杀以及其他自然和人为事件正在提供 创伤和压力的影响超越祖先产生并影响心理健康的证据 在后代。补救父母的行为，受到压力和减轻妊娠压力的扰动 他们因停止这种压力的遗产而受到关注。相比之下，关于如何 在受影响后代的概念之前发生的父亲压力的遗产。填补这个空白 知识，我们必须首先了解压力引起的父亲精子扰动神经生物学的改变 和精神健康。有了这种意图，我们的目标是确定细胞类型的特定后代神经生物学 受到应力诱导的精子RNA的改变的影响，而精子RNA已成为一种机制 父亲血统将压力遗产给后代。为了实现这一目标，我们依靠我们的经验 研究小鼠父亲压力，学习和记忆的遗产，并以未发表的数据为基础 证明从暴露于雄性小鼠的精子中注射RNA。 导致成年后的灭绝学习缺陷。开始我们对神经生物学的调查 可能是灭绝学习中这些缺陷的基础的机制，由精子中的RNA置于运动中 暴露于应力时，我们提出了对糖皮质激素受体（GRS）的重点 （IL-PFC），IL-PFC中神经元的基于乳酸的活性以及IL-PFC的发展。我们的重点是形状 根据以下背景。首先，IL-PFC对于灭绝学习很重要。第二，基于表观遗传学 GR基因的调节在研究了代际的研究中受到了最大的关注 人类和啮齿动物的虐待护理和妊娠压力引起的压力遗产。第三， 星形胶质细胞和神经元之间的基于乳酸的信号是一种重要的交流方式 这些细胞类型在学习和记忆中起作用，并且在产前压力中受到后代的扰动。第四， 由于贫困的护理和 妊娠压力在成年期间后代的行为使行为脱轨。在这种背景的动机中，我们 假设灭绝学习中的缺陷被小鼠精子中包含的RNA运动 暴露于压力结果，部分原因是IL-PFC中的GR可用性改变，基于乳酸的活性破坏了 IL-PFC神经元，成年IL-PFC的不成熟。为了检验这一假设，我们将使用生物化学， 分子遗传学，发育生物学和对神经元活性的体内操纵，重点是 由胚胎产生的动物的pfc，来自暴露于压力的雄性小鼠精子的RNA已是 注射。通过细胞和特定区域的研究，我们的工作将提供有关压力如何的新见解 诱导的精子RNA改变被转化为神经生物学遗产，可能具有翻译 通过确定可以针对治疗的生物学来减轻此类遗产负担的影响。