The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics
Lukas M. WeberHeena R. DivechaMatthew N. TranSang Ho KwonAbby SpanglerKelsey D. MontgomeryMadhavi TippaniRahul BharadwajJoel E. KleinmanStephanie C. PageThomas M. HydeLeonardo Collado‐TorresKristen R. MaynardKeri MartinowichStephanie C. Hicks
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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.Keywords:
Locus coeruleus
Human brain
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Objective To explore the development of locus coeruleus neurons in human fetus and supply morphological basis to selecting fitter embryoml of locus coeruleus cells in fetal locus coeruleus transplanted into transected spinal cord.Method The development of locus coeruleus neurons in 4￣ 8 monthes human fetus with the Nissl staining in this experiment was observed sys tematically.Result The locus coeruleus neurons had beenfound at the fourth month embryon.The numberof locus coeruleus neurons decreased graduallywith fetal ages. The body of locus coeruleusneurons was getting small to big. The locuscoeruleus neuron was round, oval, Pyra￣l,spindle and angular in shape. The density ofneurons increased in early embryon and decreasesgradully with fetal ages in late embryonic. The neurons are mainly located in dorsal of locuscoeruleus.Conclusion The neurons of locus coeruleus inhuman embryon of the foutth month seems tO befitter for graft.
Locus coeruleus
Nissl body
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The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.
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