Sensory input, sex, and function shape hypothalamic cell type development

Mammalian behavior and physiology undergo dramatic changes in early life. Young animals rely on conspecifics to meet their needs and start displaying nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviors develop during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioral control have been identified16. These data reveal a remarkable diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioral or physiological function of the corresponding cell types. We identify key stages of preoptic development, including early diversification, perinatal emergence of sex differences, postnatal maturation and refinement of signaling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide novel insights into the development of neurons controlling homeostatic functions and social behaviors and lay ground for examining the dynamics of these functions in early life. To build a transcriptional atlas of POA development, we performed droplet-based paired snRNA-seq and snATAC-seq at nine ages from E14 to P65, using the 10x Multiome kit, separately in males and females. We performed POA multiome sequencing on mutant and littermate control strains as well, focusing on mutants that affect specific sensory modalities, as well as dark-reared animals. In our initial submission to GEO, we are uploading only GEX (i.e. snRNA-seq) data; ATAC-seq data will follow.哺乳动物的行为与生理在生命早期会经历剧烈变化。幼崽依赖同种个体满足自身需求，并分别在断奶期与青春期开始展现营养独立性以及性别特异性社交行为。目前尚不明确调控稳态功能与社交行为的神经元群体在这些发育转变过程中是如何成熟的。我们采用配对转录组与染色质开放性谱分析技术，对下丘脑视前区（hypothalamic preoptic region）内的神经元群体发育轨迹进行了研究——该脑区中已被鉴定出在生理与行为调控中发挥关键作用的细胞类型[16]。本研究的数据揭示了一类由动物性别、对应细胞类型的脑区定位以及其行为/生理功能共同塑造的发育轨迹的显著多样性。我们鉴定出了视前区发育的关键阶段，包括早期细胞多样化、性别差异的围产期出现、出生后信号网络的成熟与精细化，以及在断奶期与青春期加速出现的非线性转录组变化。我们对多种感觉通路突变体的视前区发育情况进行了评估，发现犁鼻感觉在视前区细胞类型成熟的时序调控中发挥核心作用。本研究结果为调控稳态功能与社交行为的神经元发育研究提供了全新视角，并为探索生命早期这些功能的动态变化奠定了基础。为构建视前区（POA）发育的转录组图谱，我们使用10x Multiome试剂盒，分别对雄性与雌性小鼠在胚胎第14天（E14）至出生后第65天（P65）的9个时间点开展了基于微滴技术的配对单细胞核RNA测序（snRNA-seq）与单细胞核转座酶可及性测序（snATAC-seq）。我们同时对影响特定感觉模态的突变体及其同窝对照品系，以及暗饲养动物开展了视前区多组学测序。在本次向基因表达综合数据库（GEO）提交的初始数据中，我们仅上传了基因表达（GEX，即snRNA-seq）数据；染色质转座酶可及性测序（ATAC-seq）数据将后续补充。