The impact of early life stress on the immature primate amygdala: influence on mental health trajectories

早期生活压力对未成熟灵长类杏仁核的影响：对心理健康轨迹的影响

• 批准号: 10442727
• 负责人: JUDY L CAMERON
• 金额: $ 19.35万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442727
• 关键词: Adolescence; Adolescent; Affect; Age; Age-Months; Amygdaloid structure; Animals; Autopsy; Basal Ganglia; Behavioral; Birth; Brain; Caregivers; Cell Death; Cell Nucleus; Cell Size; Cell physiology; Cells; Child; Childhood; Complex; Data; Development; Down-Regulation; Emotional; Environment; Event; Freezing; Functional disorder; Gene Expression; Genes; Glutamates; Growth; Histologic; Human; Impairment; Infant; Interruption; Learning; Life; Link; Maternal Deprivation; Measures; Mental Health; Mental disorders; Messenger RNA; Microarray Analysis; Monkeys; Mutation; Neurons; Onset of illness; Pattern; Play; Primates; Rodent; Role; Shapes; Social Behavior; Social Development; Social Functioning; Social Interaction; Structure; Time; TimeLine; Transcript; behavioral outcome; cell growth; cohort; deprivation; early life adversity; early life stress; human data; indexing; infancy; infant animal; learned behavior; mental function; migration; neuroblast; neuronal cell body; nonhuman primate; postnatal; protein expression; relating to nervous system; social; social learning; synaptogenesis; tissue archive; young adult

In primates, the amygdala has a central role in learning and responding appropriately to social behaviors. Difficulty in social function is a feature of many psychiatric disorders, and early social difficulties may be a harbinger of disease onset. In both humans and monkeys, the amygdala matures in parallel with evolving social repertoires during a protracted period from infancy through young adulthood. Surprisingly, almost nothing is known of cellular changes underlying amygdala growth, or correlates with developing social behaviors. This proposal focuses on a unique group of immature neurons found in the postnatal primate amygdala (including human), and their potential for shaping social behavior over development. Importantly, these immature neurons do not exist in rodents. Along with several other groups, we have characterized immature neurons in the primate amygdala, and recently found that they are poised to mature to glutamatergic projection neurons. This finding is buttressed by recent post-mortem human data showing that mature neurons are added to specific amygdala nuclei in neurotypical children. We hypothesize that the path from immature to mature neurons in specific amygdala regions is interrupted by early life stress, and correlates with the development of atypical social behavioral outcomes. Early life adversity in the form of maternal deprivation potently alters social behavior and amygdala function in children and monkeys. We hypothesized that maternal deprivation would alter immature neuron growth trajectories, and recently used microarray analyses to specifically explore the immature neuron cells. We found strong, specific downregulation of genes governing neuroblast differentiation and migration in deprived infants, suggesting maturational disruption by early life events. We also found a correlation between the most strongly affected gene transcript (tbr1), and time spent in typical social behavior across all animals. To begin interpreting these genetic changes, we began to investigate cellular data from the same cohort (fixed hemisphere). Preliminary data suggest a reduced ratio of mature: immature neurons in maternally deprived infants, raising the possibility of slowed or reduced growth of immature neurons. In this proposal, we use archived tissue from two cohorts (infant and adolescent) to more fully explore: 1) cellular changes in immature neurons during transition from infancy to adolescence, 2) how early life stress impacts this trajectory, and 3) associated behavioral consequences. Aim 1: What is the normal trajectory of change in mature-to-immature neuron ratios between infancy and adolescence in normal control nonhuman primates? What cellular features (e.g. cell size, dendritic arborization, protein expression) track this? Does maternal deprivation alter this trajectory? Aim 2: Across all animals in each cohort (infant and adolescent), what neural maturation measures track duration (time spent) in typical social behaviors? Which behavioral developmental trajectories in each cohort are most correlated with typical neural maturation? With atypical neural maturation?

在灵长类动物中，杏仁核在学习和对社会做出适当反应方面发挥着核心作用 行为。社交功能困难是许多精神疾病的一个特征，早期的社交困难 可能是疾病发作的先兆。在人类和猴子中，杏仁核的成熟与 从婴儿期到成年早期，社会技能不断演变。出奇， 对于杏仁核生长背后的细胞变化或与社会发展的相关性几乎一无所知 行为。该提案重点关注出生后灵长类动物中发现的一组独特的未成熟神经元 杏仁核（包括人类）及其在发展过程中塑造社会行为的潜力。重要的是， 这些未成熟的神经元在啮齿类动物中并不存在。与其他几个小组一起，我们已经描述了 灵长类杏仁核中未成熟的神经元，最近发现它们即将成熟为谷氨酸能神经元 投射神经元。最近的人体尸检数据证实了这一发现，表明成熟的神经元 添加到神经正常儿童的特定杏仁核中。我们假设从不成熟到 特定杏仁核区域的成熟神经元会受到早期生活压力的干扰，并与 非典型社会行为结果的发展。 母亲剥夺形式的早年逆境可能会改变社会行为和杏仁核 在儿童和猴子中发挥作用。我们假设母亲的剥夺会改变未成熟的神经元 生长轨迹，最近使用微阵列分析来专门探索未成熟的神经元细胞。 我们发现控制神经母细胞分化和迁移的基因有强烈的、特异性的下调 被剥夺的婴儿，表明早期生活事件对成熟造成了干扰。我们还发现了之间的相关性 受影响最严重的基因转录本 (tbr1)，以及所有动物典型社会行为所花费的时间。 为了开始解释这些基因变化，我们开始研究来自同一队列的细胞数据（固定 半球）。初步数据表明，母性剥夺的成熟神经元与未成熟神经元的比例降低 婴儿，增加了未成熟神经元生长减慢或减少的可能性。在这个提案中，我们使用 存档两个队列（婴儿和青少年）的组织，以更全面地探索：1）未成熟细胞的变化 从婴儿期到青春期过渡期间的神经元，2) 早期生活压力如何影响这一轨迹，以及 3) 相关的行为后果。目标 1：从成熟到不成熟的正常变化轨迹是什么 正常对照非人灵长类动物婴儿期和青春期的神经元比率？蜂窝功能有哪些 （例如细胞大小、树突分枝、蛋白质表达）跟踪这个？母亲剥夺会改变这一点吗 弹道？目标 2：在每个队列的所有动物（婴儿和青少年）中，神经成熟度的衡量标准 跟踪典型社交行为的持续时间（花费的时间）？各有哪些行为发展轨迹 队列与典型的神经成熟最相关？具有非典型的神经成熟？

项目成果

Immature neurons in the primate amygdala: changes with early development and disrupted early environment.

灵长类杏仁核中的未成熟神经元：随着早期发育和早期环境的破坏而变化。

• DOI: 10.1101/2023.02.10.528076
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: McHale-Matthews,AlexandraC;DeCampo,DanielleM;Love,Tanzy;Cameron,JudyL;Fudge,JulieL
• 通讯作者: Fudge,JulieL