The role of distinct hippocampal calbindin neurons in modulating individual susceptibility to early life stress

早期生活压力是包括严重抑郁障碍在内的精神疾病的主要风险因素。然而，早期生活应激的有害影响背后的神经生物学机制仍有待阐明。申请该项目的中国和德国研究团队一直在合作进行早期应激神经生物学的机制研究，并积累了坚实而令人兴奋的数据。两个团队已在《自然神经科学》、《生物精神病学》、《神经精神药理学》等国际知名期刊上联合发表论文10余篇。这个项目的重点是钙结合蛋白，一种与神经可塑性密切相关的钙结合蛋白，与精神疾病有关。本项目结合化学遗传学、分子生物学、形态学、药理学和行为学的方法，旨在揭示关键应激介质特别是GR-FKBP51和CRHR1-Nectin-3系统对海马钙结合蛋白表达的调节以及表达钙结合蛋白的神经元亚群的活性。此外，不同的海马钙结合蛋白表达神经元亚群在早期应激损伤的突触可塑性以及情绪和认知行为中的参与也将被剖析。这项研究将为应激相关精神障碍的潜在机制和治疗靶点的发展提供新的线索。

Early-life stress is a major risk factor for psychiatric disorders including major depressive disorder. However, the neurobiological mechanisms underlying the deleterious effects of early-life stress remain to be elucidated. The Chinese and German research teams applying for this project have been collaborating on the mechanistic studies of the neurobiology of early-life stress, and have accumulated solid and exciting data. The two teams have jointly published over 10 papers in internationally renowned journals including Nature Neuroscience, Biological Psychiatry and Neuropsychopharmacology. This project focuses on calbindin, a calcium-binding protein closely related to neural plasticity and implicated in psychiatric disorders. Combining chemogenetic, molecular, morphological, pharmacological, and behavioral approaches, this project aims to reveal the regulation of hippocampal calbindin protein expression and the activity of calbindin-expressing neuronal subpopulations by key stress mediators especially the GR-FKBP51 and CRHR1-nectin-3 systems. Moreover, the involvement of distinct hippocampal calbindin-expressing neuronal subpopulations in early-life stress-impaired synaptic plasticity as well as emotional and cognitive behavior will be dissected. This study will shed new light on the underlying mechanisms of stress-related psychiatric disorders and the development of therapeutic targets.