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严重的不利影响。早期生活的压力会导致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。在人类研究中有迹象表明，儿童的压力和创伤与语言障碍和学业成绩差距有关。然而，一个主要的问题仍然没有解决：发育压力是如何影响学习过程的，以及大脑中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方面都有重大影响，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，但通常具有破坏肠道中“有益”细菌的副作用。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的持久变化；2)肠道细菌群落的破坏是否会引起压力并损害学习。了解如何预防和调节这些早期生活压力的影响对促进终身教育成就至关重要。鸣禽和人类都有独特的学习发声的能力，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，鸣声是一种强大的、可量化的学习方法，鸣禽在早期生活压力后表现出受损的鸣声学习能力。该项目将以斑胸草雀作为鸣禽模型系统，研究发育压力对学习、大脑和微生物组的影响。将对斑胸草雀雏鸟进行不同的治疗，要么口服皮质酮，以模拟慢性应激的激素和生理影响，要么进行媒介控制。研究人员还将对一组鸟类使用抗生素，以测试微生物组的扰动是否会引起影响学习的应激反应。在治疗阶段之后，幼斑胸草雀将被安置在一个成年雄性斑胸草雀导师的身边。研究者将在60天的歌曲学习期间持续记录幼鸟发出的所有声音，以量化和比较不同处理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收集神经组织，以及与歌曲发育无关的区域，以评估脑核中的基因表达和RNAseq治疗。定期收集粪便样本进行16S测序，分析微生物组成。综上所述，这些关于鸣禽早期生活压力影响的实验将揭示压力、微生物群和学习之间的潜在联系。该奖项反映了美国国家科学基金会的法定使命，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.