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 行为。社会功能的困难是许多精神疾病和早期社会困难的特征 可能是疾病发作的预兆。在人类和猴子中，杏仁核与 从婴儿期到成年期的旷日持久，不断发展社会曲目。出奇， 几乎没有任何了解杏仁核增长的细胞变化，或与发展社会相关的 行为。该提案重点是在产后灵长类动物中发现的独特的未成熟神经元 杏仁核（包括人）及其在发展上塑造社会行为的潜力。重要的是， 这些未成熟的神经元不存在于啮齿动物中。与其他几个小组一起，我们还表征了 灵长类动物杏仁核中未成熟的神经元，最近发现它们已准备成熟到谷氨酸能 投射神经元。这一发现受到最近验尸的人类数据的支持，表明成熟的神经元 在神经型儿童中添加到特定的杏仁核核中。我们假设从不成熟到 特定杏仁核区域中的成熟神经元被早期的生命压力中断，与 发展非典型社会行为成果。 孕产妇剥夺形式的早期逆境有效地改变了社会行为和杏仁核 儿童和猴子的功能。我们假设孕产妇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。 我们发现控制神经细胞分化和迁移的基因的强烈，具体的下调 被剥夺的婴儿，暗示着早期生活事件的成熟破坏。我们还发现 最受影响的基因转录本（TBR1），以及所有动物典型的社会行为花费的时间。 为了开始解释这些遗传变化，我们开始研究来自同一队列的细胞数据（固定 半球）。初步数据表明成熟的比率降低：在母体剥夺中未成熟的神经元 婴儿，增加了未成熟神经元生长减慢或减少的可能性。在此提案中，我们使用 从两个队列（婴儿和青少年）到更充分探索的存档组织：1）未成熟的细胞变化 从婴儿期到青春期过渡期间的神经元，2）生命早期压力如何影响这一轨迹，3） 相关的行为后果。 AIM 1：成熟到成熟的变化的正常轨迹是什么 正常对照非人类灵长类动物的婴儿期和青春期之间的神经元比？什么蜂窝特征 （例如细胞大小，树突状树博化，蛋白质表达）跟踪这一点？孕产妇的剥夺会改变这种情况吗 弹道？目标2：在每个队列中的所有动物（婴儿和青少年）中，哪些神经成熟度量 跟踪典型社会行为的持续时间（花费的时间）？每个行为发展轨迹 队列与典型的神经成熟最相关吗？与非典型神经成熟？

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