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、大屠杀和其他自然和人为事件正在提供 有证据表明创伤和压力的影响超出了祖辈的范围并影响心理健康 在后代中。纠正受压力困扰的父母行为并减轻怀孕期间的压力 因其在阻止此类压力遗留问题方面的效用而受到关注。相比之下，人们对如何 停止在受影响的后代受孕之前发生的父亲压力的遗留问题。为了填补这一空白 知识，我们必须首先了解压力引起的父亲精子的改变如何扰乱神经生物学 并破坏心理健康。出于这个目的，我们的目标是确定细胞类型特异性后代神经生物学如何 受到压力引起的精子 RNA 变化的影响，这种变化已成为一种机制，通过这种机制 父系血统将压力遗传给后代。为了实现这一目标，我们依靠我们的经验 研究父亲压力、小鼠学习和记忆的遗产，并以未发表的数据为基础 证明将受到压力的雄性小鼠精子中的 RNA 注射到单细胞受精卵中 导致成年后的灭绝学习能力出现缺陷。开始我们对神经生物学的研究 精子中的 RNA 启动了消除学习缺陷的潜在机制 暴露于压力下，我们建议重点关注边缘下前额皮质中的糖皮质激素受体（GR） (IL-PFC)、IL-PFC 中神经元的乳酸活性以及 IL-PFC 的发育。我们的焦点已成型 通过以下背景。首先，IL-PFC 对于消退学习很重要。二、基于表观遗传学 在研究代际遗传的研究中，GR基因的调控受到了最多的关注。 人类和啮齿类动物因虐待性护理和妊娠压力而产生的压力遗留问题。第三， 星形胶质细胞和神经元之间基于乳酸的信号传导是星形胶质细胞和神经元之间沟通的重要模式 这些细胞类型在学习和记忆中发挥作用，并且会受到产前压力的干扰。第四， 由于缺乏照顾和照顾，人类和啮齿类动物的全氟碳化物的发育发生了改变 妊娠压力会使后代成年后的行为脱轨。在这样的背景下，我们 假设小鼠精子中含有的 RNA 启动了灭绝学习的缺陷 暴露于压力的部分原因是 IL-PFC 中 GR 可用性的改变，破坏了基于乳酸的活性 IL-PFC 神经元和成人 IL-PFC 的不成熟。为了检验这个假设，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- 动物的 PFC 是由胚胎产生的，其中来自暴露于压力的雄性小鼠精子的 RNA 已被注入 注射。通过特定于细胞和区域的研究，我们的工作将提供关于压力如何- 精子 RNA 的诱导改变被转化为神经生物学遗产，并且可能具有翻译作用 通过确定可以作为治疗目标的生物学来减轻此类遗产的负担。