Abstract
As the most important organ in our bodies, the brain plays a critical role in deciding sex-related differential features; however, the underlying neural circuitry basis remains unclear. Here, we used a cell-type-specific rabies virus-mediated monosynaptic tracing system to generate a sex differences-related whole-brain input atlas of locus coeruleus noradrenaline (LC-NE) neurons. We developed custom pipelines for brain-wide comparisons of input sources in both sexes with the registration of the whole-brain data set to the Allen Mouse Brain Reference Atlas. Among 257 distinct anatomical regions, we demonstrated the differential proportions of inputs to LC-NE neurons in male and female mice at different levels. Locus coeruleus noradrenaline neurons of two sexes showed general similarity in the input patterns, but with differentiated input proportions quantitatively from major brain regions and diverse sub-regions. For instance, inputs to male LC-NE neurons were found mainly in the cerebrum, interbrain, and cerebellum, whereas inputs to female LC-NE neurons were found in the midbrain and hindbrain. We further found that specific subsets of nuclei nested within sub-regions contributed to overall sex-related differences in the input circuitry. Furthermore, among the totaled 123 anatomical regions with proportion of inputs >0.1%, we also identified 11 sub-regions with significant statistical differences of total inputs between male and female mice, and seven of them also showed such differences in ipsilateral hemispheres. Our study not only provides a structural basis to facilitate our understanding of sex differences at a circuitry level but also provides clues for future sexually differentiated functional studies related to LC-NE neurons.
Highlights
Sex differences, i.e., differences between male and female organisms, are prevalent among a number of organs, including the liver, kidney, muscles, gut, and brain (De Vries and Forger, 2015)
To eliminate the effect originated from the process of mixing two rAAVs, such as inaccurate regulation of mixing ratios and uneven distribution of virions within mixtures, we took advantage of the viral co-packaging strategy according to our previous method and used co-packaged lAAV-DIO-GT/RG as helper for monosynaptic tracing
Our study provided the brain-wide quantitative analysis of direct inputs to locus coeruleus noradrenaline (LC-NE) neurons in male and female mice and generated the sex-related differential whole-brain input atlas for the first time
Summary
I.e., differences between male and female organisms, are prevalent among a number of organs, including the liver, kidney, muscles, gut, and brain (De Vries and Forger, 2015). An exponentially increasing body of evidence indicated that striking sex differences exist among multiple behaviors, such as cognitive function, fear, stress, and pain (Andreano and Cahill, 2009; Farrell et al, 2013; Bangasser et al, 2016; Sorge and Strath, 2018), as well as several neurological and psychiatric diseases, such as Parkinson’s disease, Alzheimer’s disease, and epilepsy (Zagni et al, 2016). Several clinical studies demonstrate that compared with men, women were at 2–3 times higher risk of developing migraine, post-traumatic stress disorder, and Alzheimer’s disease (Olff, 2017; Vetvik and MacGregor, 2017; Laws et al, 2018); males were more prone to suffer from diseases such as Parkinson’s disease and autism spectrum disorder than females (Zagni et al, 2016). Numerous previous studies have shown that multiple brain regions, which are involved in these functions and in psychiatric disorders, such as the hypothalamus, bed nuclei of the stria terminalis (BST), hippocampal CA1, CA3, and dentate gyrus and locus coeruleus (LC), are sexually differentiated on both structural and functional levels (Hutton et al, 1998; De Vries and Simerly, 2002; Shah et al, 2004; Bangasser et al, 2016; Yagi and Galea, 2018)
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