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Locus coeruleus: a new look at the blue spot

Abstract

The locus coeruleus (LC), or ‘blue spot’, is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.

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Fig. 1: The blue spot: past discoveries and future horizons.
Fig. 2: Evolving views of the LC synaptic architecture and functional organization.
Fig. 3: GANE release creates local NA ‘hot spots’ and alters network processing: the network GANE model.

References

  1. Totah, N. K. B., Logothetis, N. K. & Eschenko, O. Noradrenergic ensemble-based modulation of cognition over multiple timescales. Brain Res. 1709, 50–66 (2019).

    CAS  PubMed  Google Scholar 

  2. Likhtik, E. & Johansen, J. P. Neuromodulation in circuits of aversive emotional learning. Nat. Neurosci. 22, 1586–1597 (2019).

    CAS  PubMed  Google Scholar 

  3. Chandler, D. J. et al. Redefining noradrenergic neuromodulation of behavior: impacts of a modular locus coeruleus architecture. J. Neurosci. 39, 8239–8249 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kebschull, J. M. et al. High-throughput mapping of single-neuron projections by sequencing of barcoded RNA. Neuron 91, 975–987 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Robertson, S. D., Plummer, N. W. & Jensen, P. Uncovering diversity in the development of central noradrenergic neurons and their efferents. Brain Res. 1641, 234–244 (2016).

    CAS  PubMed  Google Scholar 

  6. Schwarz, L. A. et al. Viral-genetic tracing of the input–output organization of a central noradrenaline circuit. Nature 524, 88–92 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Uematsu, A. et al. Modular organization of the brainstem noradrenaline system coordinates opposing learning states. Nat. Neurosci. 20, 1602–1611 (2017). This behavioural study in rats reveals a modular organization of LC with projection and behaviour-specific cell populations.

    CAS  PubMed  Google Scholar 

  8. 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.0010-20.202 (2020).

    Google Scholar 

  9. Agster, K. L., Mejias-Aponte, C. A., Clark, B. D. & Waterhouse, B. D. Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. J. Comp. Neurol. 521, 2195–2207 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lewis, D. A. & Morrison, J. H. Noradrenergic innervation of monkey prefrontal cortex: a dopamine-β-hydroxylase immunohistochemical study. J. Comp. Neurol. 282, 317–330 (1989).

    CAS  PubMed  Google Scholar 

  11. Morrison, J. H. & Foote, S. L. Noradrenergic and serotoninergic innervation of cortical, thalamic, and tectal visual structures in Old and New World monkeys. J. Comp. Neurol. 243, 117–138 (1986).

    CAS  PubMed  Google Scholar 

  12. 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). This study reveals the modular organization of LC with projection and behaviour-specific cell populations.

    PubMed  PubMed Central  Google Scholar 

  13. Waterhouse, B. D. & Chandler, D. J. Heterogeneous organization and function of the central noradrenergic system. Brain Res. 1641, v–x (2016).

    CAS  PubMed  Google Scholar 

  14. 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). This comprehensive study uses anatomical, molecular and electrophysiological approaches to demonstrate the heterogeneity of LC cell populations projecting to prefrontal or motor cortices.

    CAS  PubMed  Google Scholar 

  15. Chandler, D. J., Waterhouse, B. D. & Gao, W. J. New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front. Neural Circuits 8, 53 (2014).

    PubMed  PubMed Central  Google Scholar 

  16. Zerbi, V. et al. Rapid reconfiguration of the functional connectome after chemogenetic locus coeruleus activation. Neuron 103, 702–718.e5 (2019).

    CAS  PubMed  Google Scholar 

  17. Feng, J. et al. A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine. Neuron 102, 745–761.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Breton-Provencher, V. & Sur, M. Active control of arousal by a locus coeruleus GABAergic circuit. Nat. Neurosci. 22, 218–228 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Aston-Jones, G., Ennis, M., Pieribone, V. A., Nickell, W. T. & Shipley, M. T. The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234, 734–737 (1986).

    CAS  PubMed  Google Scholar 

  22. Luppi, P. H., Aston-Jones, G., Akaoka, H., Chouvet, G. & Jouvet, M. Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience 65, 119–160 (1995).

    CAS  PubMed  Google Scholar 

  23. Aston-Jones, G., Chen, S., Zhu, Y. & Oshinsky, M. L. A neural circuit for circadian regulation of arousal. Nat. Neurosci. 4, 732–738 (2001).

    CAS  PubMed  Google Scholar 

  24. Takeuchi, T. et al. Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537, 357–362 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Castren, E., Thoenen, H. & Lindholm, D. Brain-derived neurotrophic factor messenger RNA is expressed in the septum, hypothalamus and in adrenergic brain stem nuclei of adult rat brain and is increased by osmotic stimulation in the paraventricular nucleus. Neuroscience 64, 71–80 (1995).

    CAS  PubMed  Google Scholar 

  26. Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M. & Varon, S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17, 2295–2313 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Koylu, E. O., Smith, Y., Couceyro, P. R. & Kuhar, M. J. CART peptides colocalize with tyrosine hydroxylase neurons in rat locus coeruleus. Synapse 31, 309–311 (1999).

    CAS  PubMed  Google Scholar 

  28. Simpson, K. L., Waterhouse, B. D. & Lin, R. C. Origin, distribution, and morphology of galaninergic fibers in the rodent trigeminal system. J. Comp. Neurol. 411, 524–534 (1999).

    CAS  PubMed  Google Scholar 

  29. Xu, Z. Q., Shi, T. J. & Hokfelt, T. Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on the galanin-R1 and -R2 receptors. J. Comp. Neurol. 392, 227–251 (1998).

    CAS  PubMed  Google Scholar 

  30. Devoto, P., Flore, G., Saba, P., Fa, M. & Gessa, G. L. Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus. BMC Neurosci. 6, 31 (2005).

    PubMed  PubMed Central  Google Scholar 

  31. Devoto, P., Flore, G., Pani, L. & Gessa, G. L. Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex. Mol. Psychiatry 6, 657–664 (2001). This study is an early demonstration that LC axonal terminals can co-release dopamine and noradrenaline.

    CAS  PubMed  Google Scholar 

  32. Perez, S. E., Wynick, D., Steiner, R. A. & Mufson, E. J. Distribution of galaninergic immunoreactivity in the brain of the mouse. J. Comp. Neurol. 434, 158–185 (2001).

    CAS  PubMed  Google Scholar 

  33. Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012).

    CAS  PubMed  Google Scholar 

  34. Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).

    CAS  PubMed  Google Scholar 

  35. Wang, H., Jing, M. & Li, Y. Lighting up the brain: genetically encoded fluorescent sensors for imaging neurotransmitters and neuromodulators. Curr. Opin. Neurobiol. 50, 171–178 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Beas, B. S. et al. The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nat. Neurosci. 21, 963–973 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kempadoo, K. A., Mosharov, E. V., Choi, S. J., Sulzer, D. & Kandel, E. R. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc. Natl Acad. Sci. USA 113, 14835–14840 (2016).

    CAS  PubMed  Google Scholar 

  38. Wagatsuma, A. et al. Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. Proc. Natl Acad. Sci. USA 115, E310–E316 (2018).

    CAS  PubMed  Google Scholar 

  39. Pomrenze, M. B. et al. Dissecting the roles of GABA and neuropeptides from rat central amygdala CRF neurons in anxiety and fear learning. Cell Rep. 29, 13–21.e14 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tillage, R. P. et al. Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors. Brain Struct. Funct. 225, 785–803 (2020).

    CAS  PubMed  Google Scholar 

  41. Sonneborn, A. & Greene, R. W. The norepinephrine transporter regulates dopamine-dependent synaptic plasticity in the mouse dorsal hippocampus. Preprint at bioRxiv https://doi.org/10.1101/793265 (2019).

    Article  Google Scholar 

  42. Berridge, C. W. & Abercrombie, E. D. Relationship between locus coeruleus discharge rates and rates of norepinephrine release within neocortex as assessed by in vivo microdialysis. Neuroscience 93, 1263–1270 (1999).

    CAS  PubMed  Google Scholar 

  43. Florin-Lechner, S. M., Druhan, J. P., Aston-Jones, G. & Valentino, R. J. Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus. Brain Res. 742, 89–97 (1996).

    CAS  PubMed  Google Scholar 

  44. Venton, B. J. & Cao, Q. Fundamentals of fast-scan cyclic voltammetry for dopamine detection. Analyst 145, 1158–1168 (2020).

    CAS  PubMed  Google Scholar 

  45. Bucher, E. S. & Wightman, R. M. Electrochemical analysis of neurotransmitters. Annu. Rev. Anal. Chem. 8, 239–261 (2015).

    CAS  Google Scholar 

  46. Schmidt, K. T. & McElligott, Z. A. Dissecting the catecholamines: how new approaches will facilitate the distinction between noradrenergic and dopaminergic systems. ACS Chem. Neurosci. 10, 1872–1874 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Roberts, J. G. & Sombers, L. A. Fast-scan cyclic voltammetry: chemical sensing in the brain and beyond. Anal. Chem. 90, 490–504 (2018).

    CAS  PubMed  Google Scholar 

  48. Liberzon, I. et al. Interaction of the ADRB2 gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder. JAMA Psychiatry 71, 1174–1182 (2014).

    PubMed  PubMed Central  Google Scholar 

  49. McCune, S. K. & Hill, J. M. Ontogenic expression of two α-1 adrenergic receptor subtypes in the rat brain. J. Mol. Neurosci. 6, 51–62 (1995).

    CAS  PubMed  Google Scholar 

  50. MacDonald, E. & Scheinin, M. Distribution and pharmacology of α2-adrenoceptors in the central nervous system. J. Physiol. Pharmacol. 46, 241–258 (1995).

    CAS  PubMed  Google Scholar 

  51. Scheinin, M. et al. Distribution of α2-adrenergic receptor subtype gene expression in rat brain. Mol. Brain Res. 21, 133–149 (1994).

    CAS  PubMed  Google Scholar 

  52. Civantos Calzada, B. & Aleixandre de Artinano, A. α-Adrenoceptor subtypes. Pharmacol. Res. 44, 195–208 (2001).

    CAS  PubMed  Google Scholar 

  53. Molinoff, P. B. α- and β-Adrenergic receptor subtypes properties, distribution and regulation. Drugs 28, 1–15 (1984).

    CAS  PubMed  Google Scholar 

  54. Hertz, L., Chen, Y., Gibbs, M. E., Zang, P. & Peng, L. Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders? Curr. Drug. Targets CNS Neurol. Disord. 3, 239–267 (2004).

    CAS  PubMed  Google Scholar 

  55. Nalepa, I., Kreiner, G., Bielawski, A., Rafa-Zablocka, K. & Roman, A. α1-Adrenergic receptor subtypes in the central nervous system: insights from genetically engineered mouse models. Pharmacol. Rep. 65, 1489–1497 (2013).

    CAS  PubMed  Google Scholar 

  56. 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).

    PubMed  PubMed Central  Google Scholar 

  57. Hirsch, M. R., Tiveron, M. C., Guillemot, F., Brunet, J. F. & Goridis, C. Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development 125, 599–608 (1998).

    CAS  PubMed  Google Scholar 

  58. Brunet, J. F. & Pattyn, A. Phox2 genes — from patterning to connectivity. Curr. Opin. Genet. Dev. 12, 435–440 (2002).

    CAS  PubMed  Google Scholar 

  59. Holm, P. C. et al. Crucial role of TrkB ligands in the survival and phenotypic differentiation of developing locus coeruleus noradrenergic neurons. Development 130, 3535–3545 (2003).

    CAS  PubMed  Google Scholar 

  60. Shi, M. et al. Notch–Rbpj signaling is required for the development of noradrenergic neurons in the mouse locus coeruleus. J. Cell Sci. 125, 4320–4332 (2012).

    CAS  PubMed  Google Scholar 

  61. Goridis, C. & Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat. Rev. Neurosci. 3, 531–541 (2002).

    CAS  PubMed  Google Scholar 

  62. Li, S. et al. Conversion of astrocytes and fibroblasts into functional noradrenergic neurons. Cell Rep. 28, 682–697.e687 (2019).

    CAS  PubMed  Google Scholar 

  63. Marshall, K. C., Christie, M. J., Finlayson, P. G. & Williams, J. T. Developmental aspects of the locus coeruleus–noradrenaline system. Prog. Brain Res. 88, 173–185 (1991).

    CAS  PubMed  Google Scholar 

  64. Nakamura, S., Kimura, F. & Sakaguchi, T. Postnatal development of electrical activity in the locus ceruleus. J. Neurophysiol. 58, 510–524 (1987).

    CAS  PubMed  Google Scholar 

  65. Debiec, J. & Sullivan, R. M. The neurobiology of safety and threat learning in infancy. Neurobiol. Learn. Mem. 143, 49–58 (2017).

    PubMed  Google Scholar 

  66. Caldji, C. et al. Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc. Natl Acad. Sci. USA 95, 5335–5340 (1998).

    CAS  PubMed  Google Scholar 

  67. Hassani, O. K. et al. The noradrenergic system is necessary for survival of vulnerable midbrain dopaminergic neurons: implications for development and Parkinson’s disease. Neurobiol. Aging 85, 22–37 (2020).

    CAS  PubMed  Google Scholar 

  68. Christie, M. J. Generators of synchronous activity of the locus coeruleus during development. Semin. Cell Dev. Biol. 8, 29–34 (1997).

    CAS  PubMed  Google Scholar 

  69. Bezin, L., Marcel, D., Desgeorges, S., Pujol, J. F. & Weissmann, D. Singular subsets of locus coeruleus neurons may recover tyrosine hydroxylase phenotype transiently expressed during development. Mol. Brain Res. 76, 275–281 (2000).

    CAS  PubMed  Google Scholar 

  70. Williams, J. T. & Marshall, K. C. Membrane properties and adrenergic responses in locus coeruleus neurons of young rats. J. Neurosci. 7, 3687–3694 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ennis, M. & Aston-Jones, G. Evidence for self- and neighbor-mediated postactivation inhibition of locus coeruleus neurons. Brain Res. 374, 299–305 (1986).

    CAS  PubMed  Google Scholar 

  72. Williams, J. T., North, R. A., Shefner, S. A., Nishi, S. & Egan, T. M. Membrane properties of rat locus coeruleus neurones. Neuroscience 13, 137–156 (1984).

    CAS  PubMed  Google Scholar 

  73. Bouret, S. & Sara, S. J. Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci. 28, 574–582 (2005). The authors develop the hypothesis that NA released in forebrain structures in response to prediction error promotes resetting of cortical networks and cognitive flexibility.

    CAS  PubMed  Google Scholar 

  74. Berridge, C. W. & Waterhouse, B. D. The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res. Rev. 42, 33–84 (2003).

    PubMed  Google Scholar 

  75. Berridge, C. W., Schmeichel, B. E. & Espana, R. A. Noradrenergic modulation of wakefulness/arousal. Sleep Med. Rev. 16, 187–197 (2012).

    PubMed  PubMed Central  Google Scholar 

  76. Alreja, M. & Aghajanian, G. K. Use of the whole-cell patch–clamp method in studies on the role of cAMP in regulating the spontaneous firing of locus coeruleus neurons. J. Neurosci. Methods 59, 67–75 (1995).

    CAS  PubMed  Google Scholar 

  77. Wagner-Altendorf, T. A., Fischer, B. & Roeper, J. Axonal projection-specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons. Eur. J. Neurosci. 50, 3772–3785 (2019).

    PubMed  Google Scholar 

  78. Cadwell, C. R. et al. Multimodal profiling of single-cell morphology, electrophysiology, and gene expression using Patch-seq. Nat. Protoc. 12, 2531–2553 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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.e1056 (2018).

    CAS  PubMed  Google Scholar 

  80. Arnsten, A. F. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol. Psychiatry 69, e89–e99 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Spencer, R. C. & Berridge, C. W. Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants. Neuropsychopharmacology 44, 1820–1827 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Harley, C. Noradrenergic and locus coeruleus modulation of the perforant path-evoked potential in rat dentate gyrus supports a role for the locus coeruleus in attentional and memorial processes. Prog. Brain Res. 88, 307–321 (1991).

    CAS  PubMed  Google Scholar 

  83. Sara, S. J., Vankov, A. & Herve, A. Locus coeruleus-evoked responses in behaving rats: a clue to the role of noradrenaline in memory. Brain Res. Bull. 35, 457–465 (1994).

    CAS  PubMed  Google Scholar 

  84. McGaugh, J. L. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu. Rev. Neurosci. 27, 1–28 (2004).

    CAS  PubMed  Google Scholar 

  85. Sara, S. J. & Segal, M. Plasticity of sensory responses of locus coeruleus neurons in the behaving rat: implications for cognition. Prog. Brain Res. 88, 571–585 (1991). The study is one of the first demonstrations in a behaving animal of rapid responses of LC neurons to changes in reinforcement contingencies in a formal learning protocol.

    CAS  PubMed  Google Scholar 

  86. Aston-Jones, G., Rajkowski, J. & Kubiak, P. Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance task. Neuroscience 80, 697–715 (1997).

    CAS  PubMed  Google Scholar 

  87. Jahn, C. I. et al. Dual contributions of noradrenaline to behavioural flexibility and motivation. Psychopharmacology 235, 2687–2702 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Weinshenker, D. & Schroeder, J. P. There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32, 1433–1451 (2007).

    CAS  PubMed  Google Scholar 

  89. Waterhouse, B. D. & Navarra, R. L. The locus coeruleus–norepinephrine system and sensory signal processing: A historical review and current perspectives. Brain Res. 1709, 1–15 (2019).

    CAS  PubMed  Google Scholar 

  90. Sara, S. J. & Bouret, S. Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron 76, 130–141 (2012).

    CAS  PubMed  Google Scholar 

  91. Foote, S. L., Freedman, R. & Oliver, A. P. Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex. Brain Res. 86, 229–242 (1975). This is the first demonstration in a behaving animal (in the awake monkey) that NA modulates signal to noise ratios in a sensory cortex.

    CAS  PubMed  Google Scholar 

  92. Rogawski, M. A. & Aghajanian, G. K. Modulation of lateral geniculate neurone excitability by noradrenaline microiontophoresis or locus coeruleus stimulation. Nature 287, 731–734 (1980).

    CAS  PubMed  Google Scholar 

  93. Manunta, Y. & Edeline, J. M. Noradrenergic induction of selective plasticity in the frequency tuning of auditory cortex neurons. J. Neurophysiol. 92, 1445–1463 (2004).

    CAS  PubMed  Google Scholar 

  94. Devilbiss, D. M., Page, M. E. & Waterhouse, B. D. Locus ceruleus regulates sensory encoding by neurons and networks in waking animals. J. Neurosci. 26, 9860–9872 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. McCormick, D. A. Cholinergic and noradrenergic modulation of thalamocortical processing. Trends Neurosci. 12, 215–221 (1989).

    CAS  PubMed  Google Scholar 

  96. Vazey, E. M., Moorman, D. E. & Aston-Jones, G. Phasic locus coeruleus activity regulates cortical encoding of salience information. Proc. Natl Acad. Sci. USA 115, E9439–E9448 (2018).

    CAS  PubMed  Google Scholar 

  97. Lecas, J. C. Locus coeruleus activation shortens synaptic drive while decreasing spike latency and jitter in sensorimotor cortex. Implications for neuronal integration. Eur. J. Neurosci. 19, 2519–2530 (2004).

    PubMed  Google Scholar 

  98. Bouret, S. & Sara, S. J. Locus coeruleus activation modulates firing rate and temporal organization of odour-induced single-cell responses in rat piriform cortex. Eur. J. Neurosci. 16, 2371–2382 (2002).

    PubMed  Google Scholar 

  99. McLean, J. & Waterhouse, B. D. Noradrenergic modulation of cat area 17 neuronal responses to moving visual stimuli. Brain Res. 667, 83–97 (1994).

    CAS  PubMed  Google Scholar 

  100. Waterhouse, B. D., Azizi, S. A., Burne, R. A. & Woodward, D. J. Modulation of rat cortical area 17 neuronal responses to moving visual stimuli during norepinephrine and serotonin microiontophoresis. Brain Res. 514, 276–292 (1990).

    CAS  PubMed  Google Scholar 

  101. Escanilla, O., Arrellanos, A., Karnow, A., Ennis, M. & Linster, C. Noradrenergic modulation of behavioral odor detection and discrimination thresholds in the olfactory bulb. Eur. J. Neurosci. 32, 458–468 (2010).

    PubMed  Google Scholar 

  102. Martins, A. R. & Froemke, R. C. Coordinated forms of noradrenergic plasticity in the locus coeruleus and primary auditory cortex. Nat. Neurosci. 18, 1483–1492 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Navarra, R. L., Clark, B. D., Gargiulo, A. T. & Waterhouse, B. D. Methylphenidate enhances early-stage sensory processing and rodent performance of a visual signal detection task. Neuropsychopharmacology 42, 1326–1337 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Devilbiss, D. M. & Waterhouse, B. D. The effects of tonic locus ceruleus output on sensory-evoked responses of ventral posterior medial thalamic and barrel field cortical neurons in the awake rat. J. Neurosci. 24, 10773–10785 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Devilbiss, D. M. & Waterhouse, B. D. Norepinephrine exhibits two distinct profiles of action on sensory cortical neuron responses to excitatory synaptic stimuli. Synapse 37, 273–282 (2000).

    CAS  PubMed  Google Scholar 

  106. Gelbard-Sagiv, H., Magidov, E., Sharon, H., Hendler, T. & Nir, Y. Noradrenaline modulates visual perception and late visually evoked activity. Curr. Biol. 28, 2239–2249.e2236 (2018).

    CAS  PubMed  Google Scholar 

  107. McCarley, R. W. & Hobson, J. A. Neuronal excitability modulation over the sleep cycle: a structural and mathematical model. Science 189, 58–60 (1975).

    CAS  PubMed  Google Scholar 

  108. Aston-Jones, G. & Bloom, F. E. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1, 876–886 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Carter, M. E. et al. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13, 1526–1533 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lovett-Barron, M. et al. Ancestral circuits for the coordinated modulation of brain state. Cell 171, 1411–1423.e1417 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hayat, H. et al. Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep. Sci. Adv. 6, eaaz4232 (2020).

    PubMed  PubMed Central  Google Scholar 

  112. Joshi, S., Li, Y., Kalwani, R. M. & Gold, J. I. Relationships between pupil diameter and neuronal activity in the locus coeruleus, colliculi, and cingulate cortex. Neuron 89, 221–234 (2016).

    CAS  PubMed  Google Scholar 

  113. Reimer, J. et al. Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex. Nat. Commun. 7, 13289 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Pettigrew, J. D. Pharmacologic control of cortical plasticity. Retina 2, 360–372 (1982).

    CAS  PubMed  Google Scholar 

  115. Pettigrew, J. D. & Kasamatsu, T. Local perfusion of noradrenaline maintains visual cortical plasticity. Nature 271, 761–763 (1978).

    CAS  PubMed  Google Scholar 

  116. Sullivan, R. M., Wilson, D. A. & Leon, M. Norepinephrine and learning-induced plasticity in infant rat olfactory system. J. Neurosci. 9, 3998–4006 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Neuman, R. S. & Harley, C. W. Long-lasting potentiation of the dentate gyrus population spike by norepinephrine. Brain Res. 273, 162–165 (1983).

    CAS  PubMed  Google Scholar 

  118. Stanton, P. K. & Sarvey, J. M. Blockade of norepinephrine-induced long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis. Brain Res. 361, 276–283 (1985).

    CAS  PubMed  Google Scholar 

  119. Vankov, A., Herve-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).

    CAS  PubMed  Google Scholar 

  120. Grella, S. L. et al. Locus coeruleus phasic, but not tonic, activation initiates global remapping in a familiar environment. J. Neurosci. 39, 445–455 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Hagena, H., Hansen, N. & Manahan-Vaughan, D. β-Adrenergic control of hippocampal function: subserving the choreography of synaptic information storage and memory. Cereb. Cortex 26, 1349–1364 (2016).

    PubMed  PubMed Central  Google Scholar 

  122. Lemon, N., Aydin-Abidin, S., Funke, K. & Manahan-Vaughan, D. Locus coeruleus activation facilitates memory encoding and induces hippocampal LTD that depends on β-adrenergic receptor activation. Cereb. Cortex 19, 2827–2837 (2009).

    PubMed  PubMed Central  Google Scholar 

  123. Salgado, H., Kohr, G. & Trevino, M. Noradrenergic ‘tone’ determines dichotomous control of cortical spike-timing-dependent plasticity. Sci. Rep. 2, 417 (2012).

    PubMed  PubMed Central  Google Scholar 

  124. Poe, G. R., Walsh, C. M. & Bjorness, T. E. Both duration and timing of sleep are important to memory consolidation. Sleep 33, 1277–1278 (2010).

    PubMed  PubMed Central  Google Scholar 

  125. Mather, M., Clewett, D., Sakaki, M. & Harley, C. W. Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behav. Brain Sci. 39, e200 (2016).

    PubMed  Google Scholar 

  126. Toussay, X., Basu, K., Lacoste, B. & Hamel, E. Locus coeruleus stimulation recruits a broad cortical neuronal network and increases cortical perfusion. J. Neurosci. 33, 3390–3401 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. O’Donnell, J., Ding, F. & Nedergaard, M. Distinct functional states of astrocytes during sleep and wakefulness: is norepinephrine the master regulator? Curr. Sleep Med. Rep. 1, 1–8 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. Oe, Y. et al. Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance. Nat. Commun. 11, 471 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Porter-Stransky, K. A. et al. Noradrenergic transmission at α1-adrenergic receptors in the ventral periaqueductal gray modulates arousal. Biol. Psychiatry 85, 237–247 (2019).

    CAS  PubMed  Google Scholar 

  130. Kaufman, A. M., Geiller, T. & Losonczy, A. A role for the locus coeruleus in hippocampal CA1 place cell reorganization during spatial reward learning. Neuron 105, 1018–1026.e4 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kitchigina, V., Vankov, A., Harley, C. & Sara, S. J. Novelty-elicited, noradrenaline-dependent enhancement of excitability in the dentate gyrus. Eur. J. Neurosci. 9, 41–47 (1997).

    CAS  PubMed  Google Scholar 

  132. Hansen, N. & Manahan-Vaughan, D. Hippocampal long-term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by β-adrenoreceptors and the locus coeruleus. Hippocampus 25, 1285–1298 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Hansen, N. & Manahan-Vaughan, D. Locus coeruleus stimulation facilitates long-term depression in the dentate gyrus that requires activation of β-adrenergic receptors. Cereb. Cortex 25, 1889–1896 (2015).

    PubMed  Google Scholar 

  134. Sara, S. J. Reactivation, retrieval, replay and reconsolidation in and out of sleep: connecting the dots. Front. Behav. Neurosci. 4, 185 (2010).

    PubMed  PubMed Central  Google Scholar 

  135. Ferry, B., Roozendaal, B. & McGaugh, J. L. Basolateral amygdala noradrenergic influences on memory storage are mediated by an interaction between β- and α1-adrenoceptors. J. Neurosci. 19, 5119–5123 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Clayton, E. C. & Williams, C. L. Posttraining inactivation of excitatory afferent input to the locus coeruleus impairs retention in an inhibitory avoidance learning task. Neurobiol. Learn. Mem. 73, 127–140 (2000).

    CAS  PubMed  Google Scholar 

  137. Cahill, L. Neurobiological mechanisms of emotionally influenced, long-term memory. Prog. Brain Res. 126, 29–37 (2000).

    CAS  PubMed  Google Scholar 

  138. Eschenko, O., Magri, C., Panzeri, S. & Sara, S. J. Noradrenergic neurons of the locus coeruleus are phase locked to cortical up–down states during sleep. Cereb. Cortex 22, 426–435 (2012).

    PubMed  Google Scholar 

  139. Sara, S. J. Locus coeruleus in time with the making of memories. Curr. Opin. Neurobiol. 35, 87–94 (2015).

    CAS  PubMed  Google Scholar 

  140. Bernabeu, R. et al. Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats. Proc. Natl Acad. Sci. USA 94, 7041–7046 (1997).

    CAS  PubMed  Google Scholar 

  141. O’Dell, T. J., Connor, S. A., Guglietta, R. & Nguyen, P. A. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn. Mem. 22, 461–471 (2015).

    PubMed  PubMed Central  Google Scholar 

  142. McGaughy, J., Ross, R. S. & Eichenbaum, H. Noradrenergic, but not cholinergic, deafferentation of prefrontal cortex impairs attentional set-shifting. Neuroscience 153, 63–71 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Reynaud, A. J. et al. Atomoxetine improves attentional orienting in a predictive context. Neuropharmacology 150, 59–69 (2019).

    CAS  Google Scholar 

  144. Berridge, C. W. & Spencer, R. C. Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex. Brain Res. 1641, 189–196 (2016).

    CAS  PubMed  Google Scholar 

  145. Bouret, S. & Sara, S. J. Reward expectation, orientation of attention and locus coeruleus–medial frontal cortex interplay during learning. Eur. J. Neurosci. 20, 791–802 (2004).

    PubMed  Google Scholar 

  146. Xiang, L. et al. Behavioral correlates of activity of optogenetically identified locus coeruleus noradrenergic neurons in rats performing T-maze tasks. Sci. Rep. 9, 1361 (2019).

    PubMed  PubMed Central  Google Scholar 

  147. Aston-Jones, G., Rajkowski, J. & Cohen, J. Role of locus coeruleus in attention and behavioral flexibility. Biol. Psychiatry 46, 1309–1320 (1999).

    CAS  PubMed  Google Scholar 

  148. Devauges, V. & Sara, S. J. Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res. 39, 19–28 (1990).

    CAS  PubMed  Google Scholar 

  149. Tait, D. S. et al. Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur. J. Neurosci. 25, 3719–3724 (2007).

    PubMed  Google Scholar 

  150. Snyder, K., Wang, W. W., Han, R., McFadden, K. & Valentino, R. J. Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility. Neuropsychopharmacology 37, 520–530 (2012).

    CAS  PubMed  Google Scholar 

  151. Cope, Z. A., Vazey, E. M., Floresco, S. B. & Aston Jones, G. S. DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting. Neurobiol. Learn. Mem. 161, 1–11 (2019).

    PubMed  Google Scholar 

  152. Tervo, D. G. R. et al. Behavioral variability through stochastic choice and its gating by anterior cingulate cortex. Cell 159, 21–32 (2014).

    CAS  PubMed  Google Scholar 

  153. Janitzky, K. et al. Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task. Front. Behav. Neurosci. 9, 286 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. von der Gablentz, J., Tempelmann, C., Munte, T. F. & Heldmann, M. Performance monitoring and behavioral adaptation during task switching: an fMRI study. Neuroscience 285, 227–235 (2015).

    PubMed  Google Scholar 

  155. Hermans, E. J. et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science 334, 1151–1153 (2011).

    CAS  PubMed  Google Scholar 

  156. Bouret, S. & Richmond, B. J. Sensitivity of locus ceruleus neurons to reward value for goal-directed actions. J. Neurosci. 35, 4005–4014 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Uematsu, A., Tan, B. Z. & Johansen, J. P. Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and memory. Learn. Mem. 22, 444–451 (2015).

    PubMed  PubMed Central  Google Scholar 

  158. Rajkowski, J., Majczynski, H., Clayton, E. & Aston-Jones, G. Activation of monkey locus coeruleus neurons varies with difficulty and performance in a target detection task. J. Neurophysiol. 92, 361–371 (2004).

    PubMed  Google Scholar 

  159. Kalwani, R. M., Joshi, S. & Gold, J. I. Phasic activation of individual neurons in the locus ceruleus/subceruleus complex of monkeys reflects rewarded decisions to go but not stop. J. Neurosci. 34, 13656–13669 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Varazzani, C., San-Galli, A., Gilardeau, S. & Bouret, S. Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys. J. Neurosci. 35, 7866–7877 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Borderies, N., Mattioni, J., Bornert, P., Gilardeau, S. & Bouret, S. Pharmacological evidence for the implication of noradrenaline in effort. Preprint at bioRxiv https://doi.org/10.1101/714923 (2020).

    Article  Google Scholar 

  162. Shenhav, A. et al. Toward a rational and mechanistic account of mental effort. Annu. Rev. Neurosci. 40, 99–124 (2017).

    CAS  PubMed  Google Scholar 

  163. Berridge, C. W. & Arnsten, A. F. Psychostimulants and motivated behavior: arousal and cognition. Neurosci. Biobehav. Rev. 37, 1976–1984 (2013).

    CAS  PubMed  Google Scholar 

  164. Schmidt, K. T. & Weinshenker, D. Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors. Mol. Pharmacol. 85, 640–650 (2014).

    PubMed  PubMed Central  Google Scholar 

  165. Espana, R. A., Schmeichel, B. E. & Berridge, C. W. Norepinephrine at the nexus of arousal, motivation and relapse. Brain Res. 1641, 207–216 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 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). The authors present a computational approach to modelling the relation between mode of firing of LC neurons and adaptive behavioural performance.

    CAS  PubMed  Google Scholar 

  167. Arnsten, A. F. Through the looking glass: differential noradenergic modulation of prefrontal cortical function. Neural Plast. 7, 133–146 (2000). This paper reviews experiments mainly in primates supporting the notion that optimal concentration of NA plays an important role in the cognitive function of prefrontal cortex.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Yu, A. J. & Dayan, P. Uncertainty, neuromodulation, and attention. Neuron 46, 681–692 (2005). The authors present a computational approach to support the notion that the LC-NA system responds to unexpected uncertainty in the environment.

    CAS  PubMed  Google Scholar 

  169. Nassar, M. R. et al. Rational regulation of learning dynamics by pupil-linked arousal systems. Nat. Neurosci. 15, 1040–1046 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Preuschoff, K., T Hart, B. M. & Einhauser, W. Pupil dilation signals surprise: evidence for noradrenaline’s role in decision making. Front. Neurosci. 5, 115 (2011).

    PubMed  PubMed Central  Google Scholar 

  171. Jepma, M. & Nieuwenhuis, S. Pupil diameter predicts changes in the exploration–exploitation trade-off: evidence for the adaptive gain theory. J. Cogn. Neurosci. 23, 1587–1596 (2011).

    PubMed  Google Scholar 

  172. Muller, T. H., Mars, R. B., Behrens, T. E. & O’Reilly, J. X. Control of entropy in neural models of environmental state. eLife 8, e39404 (2019).

    PubMed  PubMed Central  Google Scholar 

  173. Sales, A. C., Friston, K. J., Jones, M. W., Pickering, A. E. & Moran, R. J. Locus Coeruleus tracking of prediction errors optimises cognitive flexibility: An Active Inference model. PLoS Comput. Biol. 15, e1006267 (2019).

    PubMed  PubMed Central  Google Scholar 

  174. Raizada, R. D. & Poldrack, R. A. Challenge-driven attention: interacting frontal and brainstem systems. Front. Hum. Neurosci. 1, 3 (2008).

    PubMed  PubMed Central  Google Scholar 

  175. Giller, F., Muckschel, M., Ziemssen, T. & Beste, C. A possible role of the norepinephrine system during sequential cognitive flexibility — evidence from EEG and pupil diameter data. Cortex 128, 22–34 (2020).

    PubMed  Google Scholar 

  176. Wolff, N., Muckschel, M., Ziemssen, T. & Beste, C. The role of phasic norepinephrine modulations during task switching: evidence for specific effects in parietal areas. Brain Struct. Funct. 223, 925–940 (2018).

    CAS  PubMed  Google Scholar 

  177. Alvarez, V. A., Chow, C. C., Van Bockstaele, E. J. & Williams, J. T. Frequency-dependent synchrony in locus ceruleus: role of electrotonic coupling. Proc. Natl Acad. Sci. USA 99, 4032–4036 (2002).

    CAS  PubMed  Google Scholar 

  178. Ennis, M., Shipley, M. T., Aston-Jones, G. & Williams, J. T. Afferent control of nucleus locus ceruleus: differential regulation by ‘shell’ and ‘core’ inputs. Adv. Pharmacol. 42, 767–771 (1998).

    CAS  PubMed  Google Scholar 

  179. Cerpa, J. C., Marchand, A. R. & Coutureau, E. Distinct regional patterns in noradrenergic innervation of the rat prefrontal cortex. J. Chem. Neuroanat. 96, 102–109 (2019).

    CAS  PubMed  Google Scholar 

  180. Guedj, C. et al. Boosting norepinephrine transmission triggers flexible reconfiguration of brain networks at rest. Cereb. Cortex 27, 4691–4700 (2017).

    PubMed  Google Scholar 

  181. Dahlstroem, A. & Fuxe, K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. Suppl. 62 (Suppl. 232), 1–55 (1964). This seminal paper reports the discovery of nuclei of noradrenergic neurons in the brain.

    Google Scholar 

  182. Dahl, M. J. et al. Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nat. Hum. Behav. 3, 1203–1214 (2019).

    PubMed  PubMed Central  Google Scholar 

  183. Theofilas, P. et al. Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 13, 236–246 (2017).

    PubMed  Google Scholar 

  184. Mann, D. M. & Yates, P. O. Lipoprotein pigments — their relationship to ageing in the human nervous system. II. The melanin content of pigmented nerve cells. Brain 97, 489–498 (1974).

    CAS  PubMed  Google Scholar 

  185. Betts, M. J. et al. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain 142, 2558–2571 (2019).

    PubMed  PubMed Central  Google Scholar 

  186. Liu, K. Y. et al. Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences. Nat. Commun. 11, 1712 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Twarkowski, H. & Manahan-Vaughan, D. Loss of catecholaminergic neuromodulation of persistent forms of hippocampal synaptic plasticity with increasing age. Front. Synaptic Neurosci. 8, 30 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Weinshenker, D. Long road to ruin: noradrenergic dysfunction in neurodegenerative disease. Trends Neurosci. 41, 211–223 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Braak, H. & Del Tredici, K. Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol. 121, 589–595 (2011).

    CAS  PubMed  Google Scholar 

  190. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

    PubMed  Google Scholar 

  191. Ehrenberg, A. J. et al. Neuropathologic correlates of psychiatric symptoms in Alzheimer’s disease. J. Alzheimers Dis. 66, 115–126 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Vermeiren, Y. & De Deyn, P. P. Targeting the norepinephrinergic system in Parkinson’s disease and related disorders: The locus coeruleus story. Neurochem. Int. 102, 22–32 (2017).

    CAS  PubMed  Google Scholar 

  193. Butkovich, L. M., Houser, M. C. & Tansey, M. G. α-Synuclein and noradrenergic modulation of immune cells in Parkinson’s disease pathogenesis. Front. Neurosci. 12, 626 (2018).

    PubMed  PubMed Central  Google Scholar 

  194. Ghosh, A. et al. An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development. Alzheimers Res. Ther. 11, 59 (2019).

    PubMed  PubMed Central  Google Scholar 

  195. Henrich, M. T. et al. A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson’s disease-like pathology in neurons and glia. Acta Neuropathol. Commun. 6, 39 (2018).

    PubMed  PubMed Central  Google Scholar 

  196. Koob, G. F. Corticotropin-releasing factor, norepinephrine, and stress. Biol. Psychiatry 46, 1167–1180 (1999).

    CAS  PubMed  Google Scholar 

  197. Valentino, R. J. & Van Bockstaele, E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur. J. Pharmacol. 583, 194–203 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. McCall, J. G. et al. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87, 605–620 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Tjoumakaris, S. I., Rudoy, C., Peoples, J., Valentino, R. J. & Van Bockstaele, E. J. Cellular interactions between axon terminals containing endogenous opioid peptides or corticotropin-releasing factor in the rat locus coeruleus and surrounding dorsal pontine tegmentum. J. Comp. Neurol. 466, 445–456 (2003).

    CAS  PubMed  Google Scholar 

  200. Valentino, R. J. & Wehby, R. G. Morphine effects on locus ceruleus neurons are dependent on the state of arousal and availability of external stimuli: studies in anesthetized and unanesthetized rats. J. Pharmacol. Exp. Ther. 244, 1178–1186 (1988).

    CAS  PubMed  Google Scholar 

  201. Curtis, A. L., Leiser, S. C., Snyder, K. & Valentino, R. J. Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons. Neuropharmacology 62, 1737–1745 (2012).

    CAS  PubMed  Google Scholar 

  202. Reyes, B. A., Zitnik, G., Foster, C., Van Bockstaele, E. J. & Valentino, R. J. Social stress engages neurochemically-distinct afferents to the rat locus coeruleus depending on coping strategy. eNeuro 2, ENEURO.0042-15.2015 (2015).

    PubMed  PubMed Central  Google Scholar 

  203. 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). This study is an important example of how gender impacts the function of LC-NA system.

    CAS  PubMed  Google Scholar 

  204. Bangasser, D. A. et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol. Psychiatry 15, 896–904 (2010).

    CAS  Google Scholar 

  205. Guajardo, H. M., Snyder, K., Ho, A. & Valentino, R. J. Sex differences in µ-opioid receptor regulation of the rat locus coeruleus and their cognitive consequences. Neuropsychopharmacology 42, 1295–1304 (2017).

    CAS  PubMed  Google Scholar 

  206. Helena, C. et al. Effects of estrogen receptor α and β gene deletion on estrogenic induction of progesterone receptors in the locus coeruleus in female mice. Endocrine 36, 169–177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Brady, K. T. & Randall, C. L. Gender differences in substance use disorders. Psychiatr. Clin. North. Am. 22, 241–252 (1999).

    CAS  PubMed  Google Scholar 

  208. Clemow, D. B. & Bushe, C. J. Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients. J. Psychopharmacol. 29, 1221–1230 (2015).

    CAS  PubMed  Google Scholar 

  209. Sepede, G., Corbo, M., Fiori, F. & Martinotti, G. Reboxetine in clinical practice: a review. Clin. Ter. 163, e255–e262 (2012).

    CAS  PubMed  Google Scholar 

  210. Fukada, K. et al. l-threo-3,4-dihydroxyphenylserine (L-DOPS) co-administered with entacapone improves freezing of gait in Parkinson’s disease. Med. Hypotheses 80, 209–212 (2013).

    CAS  PubMed  Google Scholar 

  211. Doughty, B., Morgenson, D. & Brooks, T. Lofexidine: a newly FDA-approved, nonopioid treatment for opioid withdrawal. Ann. Pharmacother. 53, 746–753 (2019).

    CAS  PubMed  Google Scholar 

  212. Bowrey, H. E., James, M. H. & Aston-Jones, G. New directions for the treatment of depression: targeting the photic regulation of arousal and mood (PRAM) pathway. Depress. Anxiety 34, 588–595 (2017).

    PubMed  PubMed Central  Google Scholar 

  213. Conway, C. R. & Xiong, W. The mechanism of action of vagus nerve stimulation in treatment-resistant depression: current conceptualizations. Psychiatr. Clin. North. Am. 41, 395–407 (2018).

    PubMed  Google Scholar 

  214. Oliveira, T., Francisco, A. N., Demartini, Z. J. & Stebel, S. L. The role of vagus nerve stimulation in refractory epilepsy. Arq. Neuropsiquiatr. 75, 657–666 (2017).

    PubMed  Google Scholar 

  215. Vonck, K. et al. Vagus nerve stimulation 25 years later! What do we know about the effects on cognition? Neurosci. Biobehav. Rev. 45, 63–71 (2014).

    PubMed  Google Scholar 

  216. Swift, K. M. et al. Abnormal locus coeruleus sleep activity alters sleep signatures of memory consolidation and impairs place cell stability and spatial memory. Curr. Biol. 28, 3599–3609.e3594 (2018).

    CAS  PubMed  Google Scholar 

  217. Ribeiro, S. et al. Induction of hippocampal long-term potentiation during waking leads to increased extrahippocampal zif-268 expression during ensuing rapid-eye-movement sleep. J. Neurosci. 22, 10914–10923 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Ribeiro, S., Goyal, V., Mello, C. V. & Pavlides, C. Brain gene expression during REM sleep depends on prior waking experience. Learn. Mem. 6, 500–508 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Sara, S. J. Sleep to remember. J. Neurosci. 37, 457–463 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Poe, G. R. Sleep is for forgetting. J. Neurosci. 37, 464–473 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Booth, V. & Poe, G. R. Input source and strength influences overall firing phase of model hippocampal CA1 pyramidal cells during theta: relevance to REM sleep reactivation and memory consolidation. Hippocampus 16, 161–173 (2006).

    PubMed  PubMed Central  Google Scholar 

  222. Poe, G. R., Nitz, D. A., McNaughton, B. L. & Barnes, C. A. Experience-dependent phase-reversal of hippocampal neuron firing during REM sleep. Brain Res. 855, 176–180 (2000).

    CAS  PubMed  Google Scholar 

  223. Novitskaya, Y., Sara, S. J., Logothetis, N. K. & Eschenko, O. Ripple-triggered stimulation of the locus coeruleus during post-learning sleep disrupts ripple/spindle coupling and impairs memory consolidation. Learn. Mem. 23, 238–248 (2016).

    PubMed  PubMed Central  Google Scholar 

  224. Vanderheyden, W. M., Poe, G. R. & Liberzon, I. Trauma exposure and sleep: using a rodent model to understand sleep function in PTSD. Exp. Brain Res. 232, 1575–1584 (2014).

    PubMed  Google Scholar 

  225. Wassing, R. et al. Restless REM sleep impedes overnight amygdala adaptation. Curr. Biol. 29, 2351–2358.e4 (2019).

    CAS  PubMed  Google Scholar 

  226. Cabrera, Y., Holloway, J. & Poe, G. R. Sleep changes across the female hormonal cycle affecting memory: implications for resilient adaptation to traumatic experiences. J. Womens Health 29, 446–451 (2020).

    Google Scholar 

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Acknowledgements

Funding for the 3-day workshop that generated this Perspective was provided by a grant from the Albert and Elaine Borchard Foundation Center on International Education to G.R.P. and S.J.S.Research funding to D.M.-V.: German Research Foundation project no.: 316803389, SFB 1280/A04.

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Correspondence to Susan J. Sara.

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Glossary

Chemogenetics

Viral introduction of chemically engineered neurotransmitter receptors into neuronal membranes. These can be subsequently activated by pharmacological ligands that are specific to the receptor.

Co-transmitters

Neuromodulators released from a neuron along with a primary neurotransmitter.

Fast-scan voltammetry

Voltammetry examines fluctuations in current that are driven by variations in voltage/potential. In cyclic voltammetry, after the desired potential is reached, the potential is ramped in the opposite direction to return to the initial potential (time-locked voltage oscillations), causing the substance of interest to be oxidized and reduced in predetermined cycles. The concentration of the substance can be calculated by generating a calibration curve of current against concentration, allowing the relative concentration to be calculated within milliseconds, and thus the real-time detection of neurotransmitter concentration.

Fear extinction

Learning that a context or cue that was associated with an aversive event no longer predicts that event, and thus the fear response to that context or cue is no longer expressed.

Frequency tuning

In the auditory cortex, individual neurons exhibit a specific response pattern based on the sound frequency applied. Delivery of a set of different sound frequencies determines the frequency tuning of the neuron.

Optogenetics

Analysis via the viral introduction of light-sensitive channels or ion pumps into neuronal membranes, which subsequently can be driven by the external application of a specific light wavelength.

RNAi

RNA interference, which comprises the inhibition of gene expression or translation by silencing the target mRNA.

Terminal fields

Neural areas targeted by axonal projections.

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Poe, G.R., Foote, S., Eschenko, O. et al. Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci 21, 644–659 (2020). https://doi.org/10.1038/s41583-020-0360-9

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