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.

项目概要：饥荒、大屠杀和其他自然和人为事件提供了 有证据表明，创伤和压力的影响超出了祖先一代，并影响心理健康 在后代中。纠正父母因压力而受到干扰的行为，并减轻怀孕期间的压力 因其在阻止这种压力遗产方面的效用而受到关注。相比之下，对于如何 阻止在受影响的后代受孕之前发生的父亲压力的遗留。为了填补这一空白， 知识，我们必须首先了解压力诱导的父亲精子改变如何扰乱神经生物学 破坏心理健康有了这个意图，我们的目标是确定细胞类型特异性后代神经生物学 受到压力诱导的精子RNA改变的影响，这种改变已经成为一种机制， 父系血统会将压力遗传给后代。为了实现这一目标，我们依靠我们的经验 研究父亲压力的遗传，小鼠的学习和记忆，并建立在未发表的数据 证明了将暴露于压力下的雄性小鼠精子的RNA注射到单细胞受精卵中， 导致成年后的灭绝学习缺陷。为了开始我们的研究 精子中的RNA启动了可能导致这些灭绝学习缺陷的机制 暴露于压力，我们建议关注下边缘前额叶皮质中的糖皮质激素受体（GR （IL-PFC），IL-PFC中神经元的乳酸盐活性，以及IL-PFC的发育。 以下背景。首先，IL-PFC对灭绝学习很重要。第二，基于表观遗传学 GR基因的调控在研究代际关系的研究中受到了最多的关注 在人类和啮齿类动物中，由于虐待性护理和妊娠期压力而产生的压力遗产。第三、 星形胶质细胞和神经元之间的基于乳酸的信号传导是星形胶质细胞和神经元之间的重要通信模式。 这些细胞类型在学习和记忆中发挥作用，并在后代中受到产前压力的干扰。第四、 人类和啮齿类动物中PFC的发育发生改变， 妊娠期的压力会使后代在成年期的行为脱轨。基于这一背景，我们 假设小鼠精子中所含RNA启动了消退学习缺陷 暴露于压力的部分原因是IL-PFC中GR的可用性改变， 为了验证这一假设，我们将使用生物化学， 分子遗传学、发育生物学和神经元活动的体内操纵，重点是IL-10。 从胚胎中产生的动物PFC中，暴露于应激的雄性小鼠精子的RNA被 注射。通过细胞和区域特定的调查，我们的工作将提供新的见解如何压力- 精子RNA的诱导改变被翻译成神经生物学遗产，并可能具有翻译功能 通过确定可以治疗的生物学来减轻这种遗产的负担。