The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics

Abstract

Norepinephrine (NE) neurons in the locus coeruleus (LC) project widely throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer’s and Parkinson’s disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible formats.

Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception

“…With the ability to monitor LC action potential activity across the majority of the structure established, we next sought to determine the response of individual LC neurons to various GPCR ligands. Following transcriptomic and translatomic results for LC-NE neurons from previous studies 27 , 30 , we tested forty agonists targeting different LC-expressed GPCRs and selected eighteen of them based on an initial screen for changes in activity. We further divided these agonists into three groups according to their G protein coupling or functional implications ( Table 1 ).…”

“…Consequently, these neurons participate in a variety of brain functions including cognitive control, salience detection, memory, arousal, stress processing, and pain regulation [13][14][15][16][17][18] . Furthermore, LC-NE neurons express a diverse population of G-protein coupled receptors (GPCRs), leading to complex physiological regulation by endogenous GPCR ligands 27,28,29,30 . For example, optogenetic excitation of corticotropin-releasing factor (CRF) secreting axons in LC drive anxiety-related avoidance behaviors, while pharmacological activation of orexin receptors (OXARs) and mu-opioid receptor (MOR) in LC facilitate synaptic plasticity in hippocampus and interfere the performance in cognitive function, respectively [31][32][33] .…”

Spatiotemporal analysis of gene expression in the human dentate gyrus reveals age-associated changes in cellular maturation and neuroinflammation

“…Spot level analysis was performed as previously described 48,103,104 . Briefly, spot level quality control (QC) were evaluated using the perCellQCMetrics() function from the scuttle package v.1.6.2 R Bioconductor package 49 and low quality spots having low UMI counts, low gene counts, or high percent of mitochondrial genetic expression were dropped using the isOutlier() function of the same package (Figure S1, Figure S2).…”

“…To perform spot-level deconvolution of cell types within each gene expression spot, we used publicly available snRNA-seq data 31 . To complement the design of this study, which targeted the DG, we truncated the Franjic et al, 2022 data to only the DG (N=102,753 nuclei) for use as a reference dataset (Figure S26) 31 and using cell2location v0.1.3 Python package 65 as previously described 104 . Briefly, negative binomial regression was performed to estimate reference cell type signatures.…”

An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus

“…Recent advancements [1–3] in spatially-resolved transcriptomics (SRT) have revealed how unique patterns of gene expression map onto topography of different brain regions. These techniques have enabled molecular definition of cortical laminae in the human brain beyond classic histological definitions [4,5], topographically-organized regions of the noradrenergic locus coeruleus [6], and gestational stages of the human fetal brain [7]. Findings from these studies highlight the importance of retaining spatial context in molecular profiling for biological insight.…”