Stress, microbiome, and the physiology of learning: unraveling complex interactions in the development of a learned behavior

儿童时期的急性和慢性压力会对身心健康产生深远的有害影响。早期生活压力会导致DNA结构的改变，从而改变基因的表达方式，可能对健康和福祉产生负面影响。人类研究表明，儿童的压力和创伤与语言障碍和学校成绩差距有关。然而，一个主要的问题仍然没有解决：发展压力如何影响学习过程，以及大脑中的哪些变化是这些影响的基础？此外，新出现的证据表明，肠道中的细菌对健康的多个轴有重大影响，包括心理和行为健康。抗生素通常用于医学，特别是在儿童时期，但通常会破坏肠道中的“好”细菌。该项目旨在了解1）压力是否会导致大脑中与学习相关的基因表达发生持久变化，以及2）肠道细菌群落的破坏是否会引起压力并损害学习。了解如何预防和调解这些影响的早期生活压力是至关重要的，以促进终身教育的成就。鸣禽和人类都有学习发声的独特能力，以及与发声学习和大脑发育相关的某些基因和神经结构。此外，歌声是一种强有力的、可量化的学习方法，鸣禽在经历早期生活压力后，其歌声学习能力会受损。该项目将研究发育压力对学习，大脑和微生物组的影响，使用斑胸草雀作为鸣禽模型系统。斑胸草雀雏鸟将区别对待，口服皮质酮，模仿激素和生理作用的慢性压力，或与载体控制。研究人员还将对一部分鸟类施用抗生素，以测试微生物组的扰动是否会诱导影响学习的应激反应。在治疗阶段之后，幼年斑胸草雀将与成年雄性斑胸草雀导师一起安置。研究者将在60天的歌曲学习期内连续记录青少年发出的所有声音，以量化和比较不同治疗组的歌曲学习率和准确性。然后，研究人员将从已知参与歌曲学习的大脑区域以及与歌曲发展无关的区域收集神经组织，以评估脑核中的基因表达和RNAseq治疗。将在定期时间点采集粪便样本进行16S测序，以分析微生物组成。总之，这些关于鸣禽早期生活压力影响的实验将揭示压力、微生物组和学习之间的潜在联系。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Acute and chronic stress during childhood can have profoundly detrimental effects on physical and mental health. Early-life stress can lead to modifications to the structure of DNA, which changes the way genes are expressed, potentially leading to negative effects on health and well-being. There are hints in human studies that stress and trauma in children are associated with language impairments and achievement gaps in school. However, a major question remains unresolved: how does developmental stress affect the learning process, and what changes in the brain underlie these effects? Further, emerging evidence suggests that bacteria in the gut have major effects on multiple axes of health, including mental and behavioral health. Antibiotics are routinely used in medicine, especially during childhood, but often have the side effect of disrupting the "good" bacteria in the gut. This project aims to understand 1) whether stress causes lasting changes to learning-related gene expression in the brain and 2) whether disruptions to gut bacterial communities can induce stress and impair learning. Understanding how to prevent and mediate these effects of early-life stress is critical to fostering lifelong educational achievement. Songbirds and humans share the unique ability to learn vocalizations, as well as certain genes and neural structures associated with vocal learning and brain development. In addition, song is a robust, quantifiable measure of learning, and songbirds exhibit impaired song-learning ability after early-life stress. This project will examine the effects of developmental stress on learning, the brain, and the microbiome, using the zebra finch as a songbird model system. Zebra finch nestlings will be differentially treated either with orally administered corticosterone, to mimic the hormonal and physiological effects of chronic stress, or with a vector control. The investigator will also administer antibiotics to a subset of birds to test whether perturbations to the microbiome can induce a stress response that affects learning. After the treatment phase, juvenile zebra finches will be placed with an adult male zebra finch tutor. The investigator will continuously record all sounds produced by the juvenile for the 60-day duration of the song-learning period to quantify and compare the rate and accuracy of song learning across treatments. The investigator will then collect neural tissue from regions of the brain known to be involved in song learning, as well as regions unrelated to song development, to assess gene expression across brain nuclei and treatments with RNAseq. Fecal samples will be collected at regular time points for 16S sequencing to analyze microbial composition. Taken together, these experiments on the effects of early-life stress in songbirds will shed light on the underlying connections between stress, the microbiome, and learning.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.