Department of Genetics and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Department of Anesthesiology and Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
Cell Rep. 2018 May 22;23(8):2225-2235. doi: 10.1016/j.celrep.2018.04.054.
Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females-which we leverage to illustrate the behavioral and pharmacologic relevance of these findings-and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.
临床前研究长期以来一直集中在雄性动物身上，尽管生物学性别显然会影响某些疾病的风险，包括许多精神疾病。此类疾病通常通过靶向中枢神经系统去甲肾上腺素系统的药物来治疗。尽管去甲肾上腺素能神经元在行为和神经精神疾病模型中具有重要作用，但它们的分子特征仍存在滞后。我们对体内的小鼠去甲肾上腺素能神经元进行了分析，鉴定了超过 3000 个在其中表达的高可信度转录本，包括可用药的受体。我们发现了显著的性别表达差异，包括雌性中 EP3 受体的高表达——我们利用这一点来说明这些发现的行为和药理学相关性——以及 Slc6a15 和 Lin28b，这两个都是与重度抑郁症（MDD）相关的基因。总的来说，我们提出了一种在基线和实验条件下对蓝斑核进行转录谱分析的方法。我们的研究结果强调了临床前研究需要同时纳入男性和女性，并表明去甲肾上腺素能神经元的性别差异可能是与疾病相关的行为差异的基础。
