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

压力、微生物组和学习生理学：揭示学习行为发展过程中复杂的相互作用

• 批准号: 1918824
• 负责人: Nicole Creanza
• 金额: $ 48.56万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1918824&HistoricalAwards=false
• 关键词: Stress; microbiome; physiology; learning; unraveling

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.

儿童时期的急性和慢性压力可能会对身心健康产生深远的有害影响。早年应激可能会导致DNA结构的改变，从而改变基因的表达方式，可能会对健康和福祉造成负面影响。人类研究表明，儿童的压力和创伤与语言障碍和学业成绩差距有关。然而，一个主要的问题仍然没有得到解决：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，肠道中的细菌对多个健康轴有重大影响，包括心理和行为健康。抗生素经常用于医学，尤其是在儿童时期，但通常会产生副作用，破坏肠道中的“有益”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的持久变化，以及2)肠道细菌群落的破坏是否会导致压力和损害学习。了解如何预防和调节早期生活压力的这些影响，对于培养终身教育成就至关重要。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，歌唱是一种强有力的、可量化的学习测量手段，鸣禽在幼年应激后表现出学习歌唱的能力受损。这个项目将使用斑雀作为鸣鸟的模型系统，研究发育压力对学习、大脑和微生物群的影响。斑马雀雏鸟将被区别对待，要么口服皮质酮，以模仿慢性应激的激素和生理影响，要么使用媒介控制。研究人员还将给一组鸟类注射抗生素，以测试微生物群的扰动是否会引发影响学习的应激反应。治疗阶段结束后，幼年斑纹雀将被安置在成年雄性斑马雀导师的指导下。研究人员将在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方法的歌曲学习速度和准确性。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育无关的区域收集神经组织，以评估大脑核团和RNAseq治疗方法的基因表达。将定期采集粪便样本进行16S测序，以分析微生物组成。综上所述，这些关于鸣禽早期应激影响的实验将揭示应激、微生物群和学习之间的潜在联系。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Linking the genomic signatures of human beat synchronization and learned song in birds

将人类节拍同步的基因组特征与鸟类学习的歌曲联系起来

• DOI: 10.1098/rstb.2020.0329
• 发表时间: 2021
• 期刊: Philosophical Transactions of the Royal Society B: Biological Sciences
• 作者: Gordon, Reyna L.;Ravignani, Andrea;Hyland Bruno, Julia;Robinson, Cristina M.;Scartozzi, Alyssa;Embalabala, Rebecca;Niarchou, Maria;Cox, Nancy J.;Creanza, Nicole
• 通讯作者: Creanza, Nicole