A diverse network of pericoerulear neurons control arousal states

As the primary source of norepinephrine (NE) in the brain, the locus coeruleus (LC) regulates both arousal and stress responses1,2. However, how local neuromodulatory inputs contribute to LC function remains unresolved. Here we identify a network of transcriptionally and functionally diverse GABAergic neurons in the LC dendritic field that integrate distant inputs and modulate modes of LC firing to control arousal. We define peri-LC anatomy using viral tracing and combine single-cell RNA sequencing and spatial transcriptomics to molecularly define both LC and peri-LC cell types. We identify several cell types which underlie peri-LC functional diversity using a series of complementary approaches in behaving mice. Our findings indicate that LC and peri-LC neurons comprise transcriptionally and functionally heterogenous neuronal populations, alongside anatomically segregated features which coordinate specific influences on behavioral arousal and avoidance states. Defining the molecular, cellular and functional diversity in the LC provides a road map for understanding the neurobiological basis of arousal alongside hyperarousal-related neuropsychiatric phenotypes.作为大脑中去甲肾上腺素（norepinephrine, NE）的主要来源核团，蓝斑（locus coeruleus, LC）可调控觉醒与应激反应[1,2]。然而，局部神经调制输入如何影响蓝斑的功能这一科学问题尚未得到解决。本研究在蓝斑树突域中鉴定出一类转录组与功能均具有多样性的γ-氨基丁酸能（GABAergic）神经元网络，该网络可整合远距离输入信号，并调控蓝斑的放电模式以控制觉醒状态。我们通过病毒示踪技术（viral tracing）明确了围蓝斑的解剖结构，并结合单细胞RNA测序（single-cell RNA sequencing）与空间转录组学（spatial transcriptomics），从分子层面定义了蓝斑与围蓝斑的细胞类型。我们在自由活动小鼠模型中采用一系列互补实验手段，鉴定出了支撑围蓝斑功能多样性的多种细胞类型。本研究结果表明，蓝斑与围蓝斑神经元在转录组与功能层面均存在异质性群体，同时还具备解剖分隔的特征，这些特征可协同调控行为觉醒与回避状态。明确蓝斑的分子、细胞与功能多样性，可为理解觉醒的神经生物学基础，以及高觉醒相关神经精神表型的机制提供研究蓝图。