Samuels, E. R. & Szabadi, E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr. Neuropharmacol. 6, 235–253 (2008).
Berridge, C. W., Schmeichel, B. E. & España, R. A. Noradrenergic modulation of wakefulness/arousal. Sleep Med. Rev. 16, 187–197 (2012).
Uematsu, A. et al. Modular organization of the brainstem noradrenaline system coordinates opposing learning states. Nat. Neurosci. 20, 1602–1611 (2017).
Seo, D. & Bruchas, M. R. Polymorphic computation in locus coeruleus networks. Nat. Neurosci. 20, 1517–1519 (2017).
Loughlin, S. E., Foote, S. L. & Grzanna, R. Efferent projections of nucleus locus coeruleus: morphologic subpopulations have different efferent targets. Neuroscience 18, 307–319 (1986).
Li, Y. et al. Retrograde optogenetic characterization of the pontospinal module of the locus coeruleus with a canine adenoviral vector. Brain Res. 1641, 274–290 (2016).
Plummer, N. W. et al. An intersectional viral-genetic method for fluorescent tracing of axon collaterals reveals details of noradrenergic locus coeruleus structure. eNeuro 7, ENEURO.0010–20.2020 (2020).
Hirschberg, S., Li, Y., Randall, A., Kremer, E. J. & Pickering, A. E. Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. eLife 6, e29808 (2017).
Borodovitsyna, O., Duffy, B. C., Pickering, A. E. & Chandler, D. J. Anatomically and functionally distinct locus coeruleus efferents mediate opposing effects on anxiety-like behavior. Neurobiol. Stress 13, 100284 (2020).
Aston-Jones, G., Zhu, Y. & Card, J. P. Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: possible interneuronal pool. J. Neurosci. 24, 2313–2321 (2004).
Geerling, J. C., Shin, J.-W., Chimenti, P. C. & Loewy, A. D. Paraventricular hypothalamic nucleus: axonal projections to the brainstem. J. Comp. Neurol. 518, 1460–1499 (2010).
Reyes, B. A. S., Valentino, R. J., Xu, G. & Van Bockstaele, E. J. Hypothalamic projections to locus coeruleus neurons in rat brain. Eur. J. Neurosci. 22, 93–106 (2005).
Jüngling, K., Blaesse, P., Goedecke, L. & Pape, H.-C. Dynorphin-dependent reduction of excitability and attenuation of inhibitory afferents of NPS neurons in the pericoerulear region of mice. Front. Cell. Neurosci. 10, 61 (2016).
McCall, J. G. et al. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87, 605–620 (2015).
Shipley, M. T., Fu, L., Ennis, M., Liu, W. L. & Aston-Jones, G. Dendrites of locus coeruleus neurons extend preferentially into two pericoerulear zones. J. Comp. Neurol. 365, 56–68 (1996).
Jin, X. et al. Identification of a group of GABAergic neurons in the dorsomedial area of the locus coeruleus. PLoS ONE 11, e0146470 (2016).
Breton-Provencher, V. & Sur, M. Active control of arousal by a locus coeruleus GABAergic circuit. Nat. Neurosci. 22, 218–228 (2019).
McKinney, A. et al. Cellular composition and circuit organization of the locus coeruleus of adult mice. eLife 12, e80100 (2023).
Luskin, A. T. et al. Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding. Sci. Adv. 7, eabd3666 (2021).
Wang, H.-L. & Morales, M. Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur. J. Neurosci. 29, 340–358 (2009).
Egan, T. M., Henderson, G., North, R. A. & Williams, J. T. Noradrenaline-mediated synaptic inhibition in rat locus coeruleus neurones. J. Physiol. 345, 477–488 (1983).
Takeuchi, T. et al. Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537, 357–362 (2016).
Marzo, A., Totah, N. K., Neves, R. M., Logothetis, N. K. & Eschenko, O. Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex. J. Neurophysiol. 111, 2570–2588 (2014).
Sara, S. J. & Bouret, S. Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron 76, 130–141 (2012).
Eddine, R. et al. A concurrent excitation and inhibition of dopaminergic subpopulations in response to nicotine. Sci. Rep. 5, 8184 (2015).
Soden, M. E. et al. Anatomic resolution of neurotransmitter-specific projections to the VTA reveals diversity of GABAergic inputs. Nat. Neurosci. 23, 968–980 (2020).
Vankov, A., Hervé-Minvielle, A. & Sara, S. J. Response to novelty and its rapid habituation in locus coeruleus neurons of the freely exploring rat. Eur. J. Neurosci. 7, 1180–1187 (1995).
Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786–800 (2009).
Froemke, R. C. Plasticity of cortical excitatory–inhibitory balance. Annu. Rev. Neurosci. 38, 195–219 (2015).
Gong, R., Xu, S., Hermundstad, A., Yu, Y. & Sternson, S. M. Hindbrain double-negative feedback mediates palatability-guided food and water consumption. Cell 182, 1589–1605.e22 (2020).
Buzsáki, G. Hippocampal sharp waves: their origin and significance. Brain Res. 398, 242–252 (1986).
McCall, J. G. et al. Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior. eLife 6, e18247 (2017).
Barcomb, K., Olah, S. S., Kennedy, M. J. & Ford, C. P. Properties and modulation of excitatory inputs to the locus coeruleus. J. Physiol. 600, 4897–4916 (2022).
Morris, L. S., McCall, J. G., Charney, D. S. & Murrough, J. W. The role of the locus coeruleus in the generation of pathological anxiety. Brain Neurosci. Adv. 4, 2398212820930321 (2020).
Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).
Sciolino, N. R. et al. Natural locus coeruleus dynamics during feeding. Sci. Adv. 8, eabn9134 (2022).
Llorca-Torralba, M. et al. Chemogenetic silencing of the locus coeruleus–basolateral amygdala pathway abolishes pain-induced anxiety and enhanced aversive learning in rats. Biol. Psychiatry 85, 1021–1035 (2019).
Hashikawa, Y. et al. Transcriptional and spatial resolution of cell types in the mammalian habenula. Neuron 106, 743–758.e5 (2020).
Plummer, N. W., Scappini, E. L., Smith, K. G., Tucker, C. J. & Jensen, P. Two subpopulations of noradrenergic neurons in the locus coeruleus complex distinguished by expression of the dorsal neural tube marker Pax7. Front. Neuroanat. 11, 60 (2017).
Patterson-Cross, R. B., Levine, A. J. & Menon, V. Selecting single cell clustering parameter values using subsampling-based robustness metrics. BMC Bioinformatics 22, 39 (2021).
Mulvey, B. et al. Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus. Cell Rep. 23, 2225–2235 (2018).
Curtis, A. L., Bethea, T. & Valentino, R. J. Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31, 544–554 (2006).
Totah, N. K., Neves, R. M., Panzeri, S., Logothetis, N. K. & Eschenko, O. The locus coeruleus is a complex and differentiated neuromodulatory system. Neuron 99, 1055–1068.e6 (2018).
Alvarez, V. A., Chow, C. C., Bockstaele, E. J. V. & Williams, J. T. Frequency-dependent synchrony in locus ceruleus: Role of electrotonic coupling. Proc. Natl Acad. Sci. USA 99, 4032–4036 (2002).
Chandler, D. J., Gao, W.-J. & Waterhouse, B. D. Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices. Proc. Natl Acad. Sci. USA 111, 6816–6821 (2014).
Fu, X. et al. Polony gels enable amplifiable DNA stamping and spatial transcriptomics of chronic pain. Cell 185, 4621–4633.e17 (2022).
Zitnik, G. A. Control of arousal through neuropeptide afferents of the locus coeruleus. Brain Res. 1641, 338–350 (2016).
Torrecilla, M. et al. G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. J. Neurosci. 22, 4328–4334 (2002).
Feng, J. et al. Monitoring norepinephrine release in vivo using next-generation GRABNE sensors. Neuron 112, 1930–1942.e6 (2024).
Hiraoka, K. et al. Pattern of c-Fos expression induced by tail suspension test in the mouse brain. Heliyon 3, e00316 (2017).
Yang, D. et al. Phosphorylation of pyruvate dehydrogenase inversely associates with neuronal activity. Neuron 112, 959–971.e8 (2024).
Kuo, C.-C. et al. Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications. J. Physiol. 598, 4003–4029 (2020).
Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).
Leibowitz, S. F. Paraventricular nucleus: a primary site mediating adrenergic stimulation of feeding and drinking. Pharmacol. Biochem. Behav. 8, 163–175 (1978).
Lubejko, S. T. et al. Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation. Sci. Adv. 10, eadj9581 (2024).
Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).
Parker, K. E. et al. A paranigral VTA nociceptin circuit that constrains motivation for reward. Cell 178, 653–671.e19 (2019).
Fraklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd edn (Academic Press, 2007).
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Jin, M. et al. SMART: an open-source extension of whole brain for intact mouse brain registration and segmentation. eNeuro https://doi.org/10.1523/ENEURO.0482-21.2022 (2022).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587.e29 (2021).
DePasquale, E. A. K. et al. DoubletDecon: deconvoluting doublets from single-cell RNA-sequencing data. Cell Rep. 29, 1718–1727.e8 (2019).
Korsunsky, I., Nathan, A., Millard, N. & Raychaudhuri, S. Presto scales Wilcoxon and auROC analyses to millions of observations. Preprint at bioRxiv https://doi.org/10.1101/653253 (2019).
Bult, C. J., Blake, J. A., Smith, C. L., Kadin, J. A. & Richardson, J. E. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 47, D801–D806 (2019).
Roehr, J. T., Dieterich, C. & Reinert, K. Flexbar 3.0 – SIMD and multicore parallelization. Bioinformatics 33, 2941–2942 (2017).
Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Shang, L. & Zhou, X. Spatially aware dimension reduction for spatial transcriptomics. Nat. Commun. 13, 7203 (2022).
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).
Tepe, B. et al. Single-cell RNA-seq of mouse olfactory bulb reveals cellular heterogeneity and activity-dependent molecular census of adult-born neurons. Cell Rep. 25, 2689–2703.e3 (2018).
Gayoso, A. et al. Joint probabilistic modeling of single-cell multi-omic data with totalVI. Nat. Methods 18, 272–282 (2021).
Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015).
Privitera, M. et al. A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents. Nat. Protoc. 15, 2301–2320 (2020).
Castro, D. C. et al. An endogenous opioid circuit determines state-dependent reward consumption. Nature 598, 646–651 (2021).
Deuis, J. R., Dvorakova, L. S. & Vetter, I. Methods used to evaluate pain behaviors in rodents. Front. Mol. Neurosci. https://doi.org/10.3389/fnmol.2017.00284 (2017).
