Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Illumina]

Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors. Four adult male and four adult female mice from each of two bacTRAP lines (B6;FVB-Tg(Slc6a4-EGFP/Rpl10a)JD60Jdd/J, and B6;FVB-Tg(Slc6a2-EGFP/Rpl10a)JD1538Jdd/J) were injected with LPS or vehicle (sterile PBS) and monitored for lethargy and induction of fever. Samples were handled and hybridized in two batches counterbalanced for mouse line, sex, and LPS exposure.