Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

Vincent Breton-Provencher, Gabrielle T Drummond, Mriganka Sur, Vincent Breton-Provencher, Gabrielle T Drummond, Mriganka Sur

Abstract

The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. The LC receives input from widespread brain regions, and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE to control arousal, but also in the context of a variety of sensory-motor and behavioral functions. Despite its brain-wide effects, much about the role of LC-NE in behavior and the circuits controlling LC activity is unknown. New evidence suggests that the modular input-output organization of the LC could enable transient, task-specific modulation of distinct brain regions. Future work must further assess whether this spatial modularity coincides with functional differences in LC-NE subpopulations acting at specific times, and how such spatiotemporal specificity might influence learned behaviors. Here, we summarize the state of the field and present new ideas on the role of LC-NE in learned behaviors.

Keywords: arousal; inhibition; learned behavior; learning; locus coeruleus; neuromodulation; noradrenaline (norepinephrine).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Breton-Provencher, Drummond and Sur.

Figures

FIGURE 1
FIGURE 1
Anatomy of the LC-NE system. (A) Anatomy of the outputs originating from the LC nucleus in human and mouse. Shaded areas indicate major sub-regions that potentially send input to LC. In this illustration, we have assumed that input regions identified in mouse are similar in humans (B) Distal inputs to LC-NE neurons obtained by retrograde tracing using rabies virus targeted at LC-NE neurons in mice. Input regions are grouped by: cortex (CTX), striatum (STR), pallidum (PAL), hypothalamus (HY), amygdala (AMY), midbrain (MB), medulla (MY), and cerebellum (CB). The thickness of each line represents the strength of the input from each region. Input strength was calculated by counting the number of cells retrogradely labeled in a specific area and dividing it by the total number of retrogradely labeled neurons. Regions providing less than 0.5% of inputs were left out of this diagram. Local inputs from the pons were also excluded. PFC, prefrontal cortex; MO, motor area; SS, somatosensory area; Acb, nucleus accumbens; CP, caudoputamen; BST, bed nucleus of stria terminalis; MS/NDB, medial septal/diagonal band nucleus; MPO, medial preoptic area; DMH/PVH, dorsomedial/paraventricular nucleus; LHA, lateral hypothalamic area; ZI, zona incerta; PSTN, parasubthalamic nucleus; CEA, central amygdala; SNc, substantia nigra; MRN, midbrain reticular nucleus; IPN, interpeduncular nucleus; PAG, periaqueductal gray; SC, superior colliculus; IC, inferior colliculus; PRP, nucleus prepositus; IRN, intermediate reticular nucleus; GRN, gigantocellular reticular nucleus; SPV, spinal nucleus of the trigeminal; CBX, cerebellar cortex; and CBN, cerebellar nuclei. Data in (B) from Breton-Provencher and Sur (2019).
FIGURE 2
FIGURE 2
Circuits controlling local inhibition of LC-NE+ neurons. (A) Illustration of a coronal view of the LC and medial pericoeruleus area showing the location of LC-GABA and -NE neurons. (B) Distal inputs to LC-GABA neurons obtained by retrograde tracing using rabies virus targeted at LC-NE neurons. Input regions are grouped by: cortex (CTX), striatum (STR), pallidum (PAL), hypothalamus (HY), amygdala (AMY), midbrain (MB), medulla (MY), and cerebellum (CV). The thickness of each line represents the strength of the input from each region. Input strength was calculated by counting the number of cells retrogradely labeled in a specific area and dividing it by the total number of retrogradely labeled neurons. Regions providing less than 0.5% of inputs were left out of this diagram. Local inputs from the pons were also excluded. (C) Comparison between the input strength to LC-NE versus LC-GABA for all distal brain regions targeting the LC area. The darkness of each square in the top graph represents the fraction of input each region contributes to total input. Regions are divided between three types depending on whether they send coincident or non-coincident inputs to LC-NE or LC-GABA neurons. See Figure 1 for a list of abbreviations. Data in (B,C) from Breton-Provencher and Sur (2019).
FIGURE 3
FIGURE 3
Spatiotemporal dynamics of the LC-NE system. (A) Anatomical organization of inputs to and outputs of LC. Note, LC-GABA neurons were included in this illustration as potential mechanism for nuancing local LC-NE activity, but, so far, no data exist on the relationship between local LC-GABA and specific LC-NE outputs. (B) Spatial modularity of LC-NE release. Top – Example activity of inputs to LC-NE neurons (orange), LC-NE neurons (blue), and local LC-NE release (purple). Bottom – Local versus global release of NE in output regions is dependent on which LC-NE neurons are activated by a given input. (C) Temporal modularity of LC-NE neuromodulation. Top – activity of local NE release in two given output regions and underlying neuronal activity in each region. Note, we assume that NE release is spatially global for simplicity. We also assume that NE neuromodulation increases neuronal activity in both target regions. Bottom – Due to differential NE receptor expression in brain regions, heterogenous expression of NE receptors on different types of brain cells, or the underlying function of a specific brain region, temporal integration can be local or global.

References

    1. Arnsten A. F. T. (2011). Catecholamine influences on dorsolateral prefrontal cortical networks. Biol. Psychiatry 69 e89–e99. 10.1016/j.biopsych.2011.01.027
    1. Arnsten A. F. T., Raskind M. A., Taylor F. B., Connor D. F. (2015). The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol. Stress 1 89–99. 10.1016/j.ynstr.2014.10.002
    1. Aston-Jones G., Bloom F. E. (1981a). Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J. Neurosci. 1 876–886. 10.1523/jneurosci.01-08-00876.1981
    1. Aston-Jones G., Bloom F. E. (1981b). Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J. Neurosci. 1 887–900. 10.1523/jneurosci.01-08-00887.1981
    1. Aston-Jones G., Cohen J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28 403–450. 10.1146/annurev.neuro.28.061604.135709
    1. Aston-Jones G., Waterhouse B. (2016). Locus coeruleus: from global projection system to adaptive regulation of behavior. Brain Res. 1645 75–78. 10.1016/j.brainres.2016.03.001
    1. Aston-Jones G., Zhu Y., Card J. P. (2004). Numerous GABAergic afferents to locus ceruleus in the pericerulear dendritic zone: possible interneuronal pool. J. Neurosci. 24 2313–2321. 10.1523/JNEUROSCI.5339-03.2004
    1. Beas B. S., Wright B. J., Skirzewski M., Leng Y., Hyun J. H., Koita O., et al. (2018). The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nat. Neurosci. 21 963–973. 10.1038/s41593-018-0167-4
    1. Berridge C. W. (2008). Noradrenergic modulation of arousal. Brain Res. Rev. 58 1–17. 10.1016/j.brainresrev.2007.10.013
    1. Berridge C. W., Shumsky J. S., Andrzejewski M. E., McGaughy J. A., Spencer R. C., Devilbiss D. M., et al. (2012). Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α 1- and α 2-receptors. Biol. Psychiatry 71 467–473. 10.1016/j.biopsych.2011.07.022
    1. Boucetta S., Cissé Y., Mainville L., Morales M., Jones B. E. (2014). Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J. Neurosci. 34 4708–4727. 10.1523/JNEUROSCI.2617-13.2014
    1. Bouret S., Richmond B. J. (2009). Relation of locus coeruleus neurons in monkeys to Pavlovian and operant behaviors. J. Neurophysiol. 101 898–911. 10.1152/jn.91048.2008
    1. Bouret S., Richmond X. J. (2015). Sensitivity of locus ceruleus neurons to reward value for goal-directed actions. J. Neurosci. 35 4005–4014. 10.1523/JNEUROSCI.4553-14.2015
    1. Bouret S., Sara S. J. (2004). Reward expectation, orientation of attention and locus coeruleus-medial frontal cortex interplay during learning. Eur. J. Neurosci. 20 791–802. 10.1111/j.1460-9568.2004.03526.x
    1. Bouret S., Sara S. J. (2005). Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci. 28 574–582. 10.1016/j.tins.2005.09.002
    1. Breton-Provencher V., Sur M. (2019). Active control of arousal by a locus coeruleus GABAergic circuit. Nat. Neurosci. 22 218–228. 10.1038/s41593-018-0305-z
    1. Browning M., Behrens T. E., Jocham G., O’Reilly J. X., Bishop S. J. (2015). Anxious individuals have difficulty learning the causal statistics of aversive environments. Nat. Neurosci. 18 590–596. 10.1038/nn.3961
    1. Burgess C. P., Lak A., Steinmetz N. A., Zatka-Haas P., Bai Reddy C., Jacobs E. A. K., et al. (2017). High-yield methods for accurate two-alternative visual psychophysics in head-fixed mice. Cell Rep. 20 2513–2524. 10.1016/j.celrep.2017.08.047
    1. Carter M. E., Yizhar O., Chikahisa S., Nguyen H., Adamantidis A., Nishino S., et al. (2010). Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat. Neurosci. 13:1526. 10.1038/nn.2682
    1. Cazettes F., Reato D., Morais J. P., Renart A., Mainen Z. F. (2021). Phasic activation of dorsal raphe serotonergic neurons increases pupil size. Curr. Biol. 31 192–197.e4. 10.1016/j.cub.2020.09.090
    1. Chamba G., Weissmann D., Rousset C., Renaud B., Pujol J. F. (1991). Distribution of alpha-1 and alpha-2 binding sites in the rat locus coeruleus. Brain Res. Bull. 26 185–193. 10.1016/0361-9230(91)90225-9
    1. Chandler D. J., Jensen P., McCall J. G., Pickering A. E., Schwarz L. A., Totah N. K. (2019). Redefining noradrenergic neuromodulation of behavior: impacts of a modular locus coeruleus architecture. J. Neurosci. 39 8239–8249. 10.1523/JNEUROSCI.1164-19.2019
    1. Clayton E. C., Rajkowski J., Cohen J. D., Aston-Jones G. (2004). Phasic activation of monkey locus ceruleus neurons by simple decisions in a forced-choice task. J. Neurosci. 24 9914–9920. 10.1523/JNEUROSCI.2446-04.2004
    1. Constantinople C. M., Bruno R. M. (2011). Effects and mechanisms of wakefulness on local cortical networks. Neuron 69 1061–1068. 10.1016/j.neuron.2011.02.040
    1. Cope Z. A., Vazey E. M., Floresco S. B., Aston Jones G. S. (2019). DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting. Neurobiol. Learn. Mem. 161 1–11. 10.1016/j.nlm.2019.02.009
    1. Cox J., Pinto L., Dan Y. (2016). Calcium imaging of sleep-wake related neuronal activity in the dorsal pons. Nat. Commun. 7:10763. 10.1038/ncomms10763
    1. Dayan P., Yu A. J. (2006). Phasic norepinephrine: a neural interrupt signal for unexpected events. Netw. Comput. Neural Syst. 17 335–350. 10.1080/09548980601004024
    1. Delgado P. L., Moreno F. A. (2000). Role of norepinephrine in depression. J. Clin. Psychiatry 61 5–12.
    1. Devauges V., Sara S. J. (1990). Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res. 39 19–28. 10.1016/0166-4328(90)90118-X
    1. Devoto P., Flore G., Pani L., Gessa G. L. (2001). Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex. Mol. Psychiatry 6 657–664. 10.1038/sj.mp.4000904
    1. Devoto P., Flore G., Saba P., Fà M., Gessa G. L. (2005). 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. 10.1186/1471-2202-6-31
    1. DiNuzzo M., Mascali D., Moraschi M., Bussu G., Maugeri L., Mangini F., et al. (2019). Brain networks underlying eye’s pupil dynamics. Front. Neurosci. 13:965. 10.3389/fnins.2019.00965
    1. Egan T. M., North R. A. (1986). Actions of acetylcholine and nicotine on rat locus coeruleus neurons in vitro. Neuroscience 19 565–571. 10.1016/0306-4522(86)90281-2
    1. Eldar E., Cohen J. D., Niv Y. (2013). The effects of neural gain on attention and learning. Nat. Neurosci. 16 1146–1153. 10.1038/nn.3428
    1. Elman J. A., Panizzon M. S., Hagler D. J., Eyler L. T., Granholm E. L., Fennema-Notestine C., et al. (2017). Task-evoked pupil dilation and BOLD variance as indicators of locus coeruleus dysfunction. Cortex 97 60–69. 10.1016/j.cortex.2017.09.025
    1. Engelhard B., Finkelstein J., Cox J., Fleming W., Jang H. J., Ornelas S., et al. (2019). Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons. Nature 570 509–513. 10.1038/s41586-019-1261-9
    1. Foote S. L., Berridge C. W. (2019). New developments and future directions in understanding locus coeruleus – Norepinephrine (LC-NE) function. Brain Res. 1709 81–84. 10.1016/j.brainres.2018.09.033
    1. Friedman J. I., Adler D. N., Davis K. L. (1999). The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer’s disease. Biol. Psychiatry 46 1243–1252. 10.1016/S0006-3223(99)00232-2
    1. Gent T. C., Bandarabadi M., Herrera C. G., Adamantidis A. R. (2018). Thalamic dual control of sleep and wakefulness. Nat. Neurosci. 21 974–984. 10.1038/s41593-018-0164-7
    1. Glennon E., Carcea I., Martins A. R. O., Multani J., Shehu I., Svirsky M. A., et al. (2019). Locus coeruleus activation accelerates perceptual learning. Brain Res. 1709 39–49. 10.1016/j.brainres.2018.05.048
    1. Goldman-Rakic P. S., Lidow M. S., Gallager D. W. (1990). Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex. J. Neurosci. 10 2125–2138. 10.1523/jneurosci.10-07-02125.1990
    1. Grant S. J., Aston-Jones G., Redmond D. E. (1988). Responses of primate locus coeruleus neurons to simple and complex sensory stimuli. Brain Res. Bull. 21 401–410. 10.1016/0361-9230(88)90152-9
    1. Hangya B., Ranade S. P., Lorenc M., Kepecs A. (2015). Central cholinergic neurons are rapidly recruited by reinforcement feedback. Cell 162 1155–1168. 10.1016/j.cell.2015.07.057
    1. Hayat H., Regev N., Matosevich N., Sales A., Paredes-Rodriguez E., Krom A. J., et al. (2020). Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep. Sci. Adv. 6:eaaz4232. 10.1126/sciadv.aaz4232
    1. Hertz L., Lovatt D., Goldman S. A., Nedergaard M. (2010). Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and [Ca2+]i. Neurochem. Int. 57 411–420. 10.1016/j.neuint.2010.03.019
    1. Hervé-Minvielle A., Sara S. (1995). Rapid habituation of auditory responses of locus coeruleus cells in anaesthetized and awake rats. Neuroreport 6 1363–1368. 10.1097/00001756-199507100-00001
    1. Hirschberg S., Li Y., Randall A., Kremer E. J., Pickering A. E. (2017). Functional dichotomy in spinal-vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. Elife 6:e29808. 10.7554/eLife.29808.001
    1. Holets V. R., Hökfelt T., Rökaeus Å, Terenius L., Goldstein M. (1988). Locus coeruleus neurons in the rat containing neuropeptide Y, tyrosine hydroxylase or galanin and their efferent projections to the spinal cord, cerebral cortex and hypothalamus. Neuroscience 24 893–906. 10.1016/0306-4522(88)90076-0
    1. Jahn C. I., Gilardeau S., Varazzani C., Blain B., Sallet J., Walton M. E., et al. (2018). Dual contributions of noradrenaline to behavioural flexibility and motivation. Psychopharmacology 235 2687–2702. 10.1007/s00213-018-4963-z
    1. Jahn C. I., Varazzani C., Sallet J., Walton M. E., Bouret S. (2020). Noradrenergic but not dopaminergic neurons signal task state changes and predict reengagement after a failure. Cereb. Cortex 30 4979–4994. 10.1093/cercor/bhaa089
    1. Janitzky K., Lippert M. T., Engelhorn A., Tegtmeier J., Goldschmidt J., Heinze H. J., et al. (2015). Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task. Front. Behav. Neurosci. 9:286. 10.3389/fnbeh.2015.00286
    1. Jin X., Li S., Bondy B., Zhong W., Oginsky M. F., Wu Y., et al. (2016). Identification of a group of GABAergic neurons in the dorsomedial area of the locus coeruleus. PLoS One 11:e0146470. 10.1371/journal.pone.0146470
    1. Jodo E., Chiang C., Aston-Jones G. (1998). Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience 83 63–79. 10.1016/S0306-4522(97)00372-2
    1. Jones B. E., Moore R. Y. (1977). Ascending projections of the locus coeruleus in the rat. II. autoradiographic study. Brain Res. 127 23–53. 10.1016/0006-8993(77)90378-X
    1. Jones B. E., Yang T. −Z. (1985). The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J. Comp. Neurol. 242 56–92. 10.1002/cne.902420105
    1. Joshi S., Gold J. I. (2019). Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex. bioRxiv 2020.09.26.314831. 10.1101/2020.09.26.314831
    1. Joshi S., Li Y., Kalwani R. M., Gold J. I. (2016). Relationships between pupil diameter and neuronal activity in the locus coeruleus, colliculi, and cingulate cortex article relationships between pupil diameter and neuronal activity in the locus coeruleus, colliculi, and cingulate cortex. Neuron 89 221–234. 10.1016/j.neuron.2015.11.028
    1. Kalwani R. M., Joshi S., Gold J. I. (2014). 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. 10.1523/JNEUROSCI.2566-14.2014
    1. Kane G. A., Vazey E. M., Wilson R. C., Shenhav A., Daw N. D., Aston-Jones G., et al. (2017). Increased locus coeruleus tonic activity causes disengagement from a patch-foraging task. Cogn. Affect. Behav. Neurosci. 17 1073–1083. 10.3758/s13415-017-0531-y
    1. Kaufman A. M., Geiller T., Losonczy A. (2020). A role for the locus coeruleus in hippocampal CA1 place cell reorganization during spatial reward learning. Neuron 105 1018–1026. 10.1016/j.neuron.2019.12.029
    1. Kebschull J. M., Garcia da Silva P., Reid A. P., Peikon I. D., Albeanu D. F., Zador A. M. (2016). High-throughput mapping of single-neuron projections by sequencing of barcoded RNA. Neuron 91 975–987. 10.1016/j.neuron.2016.07.036
    1. Kempadoo K. A., Mosharov E. V., Choi S. J., Sulzer D., Kandel E. R. (2016). Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc. Natl. Acad. Sci. U.S.A. 113 14835–14840. 10.1073/pnas.1616515114
    1. Kim J., Jung A., Jeong D., Choi I., Kim K., Shin S., et al. (2016). Selectivity of neuromodulatory projections from the basal forebrain and locus ceruleus to primary sensory cortices. J. Neurosci. 36 5314–5327. 10.1523/JNEUROSCI.4333-15.2016
    1. Koylu E. O., Smith Y., Couceyro P. R., Kuhar M. J. (1999). CART peptides colocalize with tyrosine hydroxylase neurons in rat locus coeruleus. Synapse 31 309–311. 10.1002/(SICI)1098-2396(19990315)31:4<309::AID-SYN10>;2-6
    1. Krishnamurthy K., Nassar M. R., Sarode S., Gold J. I. (2017). Arousal-related adjustments of perceptual biases optimize perception in dynamic environments. Nat. Hum. Behav. 1:0107. 10.1038/s41562-017-0107
    1. Kuo C. C., Hsieh J. C., Tsai H. C., Kuo Y. S., Yau H. J., Chen C. C., et al. (2020). Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications. J. Physiol. 598 4003–4029. 10.1113/JP279557
    1. Larsen R. S., Waters J. (2018). Neuromodulatory correlates of pupil dilation. Front. Neural Circuits 12:21. 10.3389/fncir.2018.00021
    1. Lawson R. P., Bisby J., Nord C. L., Burgess N., Rees G. (2021). The computational, pharmacological, and physiological determinants of sensory learning under uncertainty. Curr. Biol. 31 163–172.
    1. Lee S. H., Dan Y. (2012). Neuromodulation of brain states. Neuron 76 209–222. 10.1016/j.neuron.2012.09.012
    1. Lee T. H., Greening S. G., Ueno T., Clewett D., Ponzio A., Sakaki M., et al. (2018). Arousal increases neural gain via the locus coeruleus-noradrenaline system in younger adults but not in older adults. Nat. Hum. Behav. 2 356–366. 10.1038/s41562-018-0344-1
    1. Li L., Feng X., Zhou Z., Zhang H., Shi Q., Lei Z., et al. (2018). Stress accelerates defensive responses to looming in mice and involves a locus coeruleus-superior colliculus projection. Curr. Biol. 28 859–871. 10.1016/j.cub.2018.02.005
    1. Loughlin S. E., Foote S. L., Bloom F. E. (1986a). Efferent projections of nucleus locus coeruleus: topographic organization of cells of origin demonstrated by three-dimensional reconstruction. Neuroscience 18 291–306. 10.1016/0306-4522(86)90155-7
    1. Loughlin S. E., Foote S. L., Grzanna R. (1986b). Efferent projections of nucleus locus coeruleus: morphologic subpopulations have different efferent targets. Neuroscience 18 307–319. 10.1016/0306-4522(86)90156-9
    1. Lovett-Barron M., Andalman A. S., Allen W. E., Vesuna S., Kauvar I., Burns V. M., et al. (2017). Ancestral circuits for the coordinated modulation of brain state. Cell 171 1411–1423. 10.1016/j.cell.2017.10.021
    1. Luque J. M., Malherbe P., Richards J. G. (1994). Localization of GABAA receptor subunit mRNAs in the rat locus coeruleus. Mol. Brain Res. 24 219–226. 10.1016/0169-328X(94)90135-X
    1. Mansour A., Fox C. A., Burke S., Meng F., Thompson R. C., Akil H., et al. (1994). Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J. Comp. Neurol. 350 412–438. 10.1002/cne.903500307
    1. Marcus J. N., Aschkenasi C. J., Lee C. E., Chemelli R. M., Saper C. B., Yanagisawa M., et al. (2001). Differential expression of Orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435 6–25. 10.1002/cne.1190
    1. Martins A. R. O., Froemke R. C. (2015). Coordinated forms of noradrenergic plasticity in the locus coeruleus and primary auditory cortex. Nat. Neurosci. 18 1483–1492. 10.1038/nn.4090
    1. McCall J. G., Al-Hasani R., Siuda E. R., Hong D. Y., Norris A. J., Ford C. P., et al. (2015). CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87 605–620. 10.1016/j.neuron.2015.07.002
    1. McCall J. G., Siuda E. R., Bhatti D. L., Lawson L. A., McElligott Z. A., Stuber G. D., et al. (2017). Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior. Elife 6:e18247. 10.7554/eLife.18247
    1. McGinley M. J., David S. V., McCormick D. A. (2015). Cortical membrane potential signature of optimal states for sensory signal detection. Neuron 87 179–192. 10.1016/j.neuron.2015.05.038
    1. Murphy P. R., O’Connell R. G., O’Sullivan M., Robertson I. H., Balsters J. H. (2014). Pupil diameter covaries with BOLD activity in human locus coeruleus. Hum. Brain Mapp. 35 4140–4154. 10.1002/hbm.22466
    1. Nassar M. R., Rumsey K. M., Wilson R. C., Parikh K., Heasly B., Gold J. I. (2012). Rational regulation of learning dynamics by pupil-linked arousal systems. Nat. Neurosci. 15:1040. 10.1038/nn.3130
    1. Nomura S., Bouhadana M., Morel C., Faure P., Cauli B., Lambolez B., et al. (2014). Noradrenalin and dopamine receptors both control cAMP-PKA signaling throughout the cerebral cortex. Front. Cell. Neurosci. 8:247. 10.3389/fncel.2014.00247
    1. Pickel V. M., Segal M., Bloom F. E. (1974). A radioautographic study of the efferent pathways of the nucleus locus coeruleus. J. Comp. Neurol. 155 15–41. 10.1002/cne.901550103
    1. Plummer N. W., Chandler D. J., Powell J. M., Scappini E. L., Waterhouse B. D., Jensen P. (2020). An intersectional viral-genetic method for fluorescent tracing of axon collaterals reveals details of noradrenergic locus coeruleus structure. eNeuro 7:ENEURO.0010-20.2020. 10.1523/ENEURO.0010-20.2020
    1. Poe G. R., Foote S., Eschenko O., Johansen J. P., Bouret S., Aston-Jones G., et al. (2020). Locus coeruleus: a new look at the blue spot. Nat. Rev. Neurosci. 21 644–659. 10.1038/s41583-020-0360-9
    1. Polack P. O., Friedman J., Golshani P. (2013). Cellular mechanisms of brain state-dependent gain modulation in visual cortex. Nat. Neurosci. 16 1331–1339. 10.1038/nn.3464
    1. Rajkowski J., Majczynski H., Clayton E., Aston-Jones G. (2004). Activation of monkey locus coeruleus neurons varies with difficulty and performance in a target detection task. J. Neurophysiol. 92 361–371. 10.1152/jn.00673.2003
    1. Reimer J., McGinley M. J., Liu Y., Rodenkirch C., Wang Q., McCormick D. A., et al. (2016). Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex. Nat. Commun. 7:13289. 10.1038/ncomms13289
    1. Reyes B. A. S., Zitnik G., Foster C., van Bockstaele E. J., Valentino R. J. (2015). Social stress engages neurochemically-distinct afferents to the rat locus coeruleus depending on coping strategy. eNeuro 2:ENEURO.0042-15.2015. 10.1523/ENEURO.0042-15.2015
    1. Sara S. J. (2009). The locus coeruleus and noradrenergic modulation of cognition. Nat. Rev. Neurosci. 10 211–223. 10.1038/nrn2573
    1. Sara S. J., Bouret S. (2012). Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron 76 130–141. 10.1016/j.neuron.2012.09.011
    1. Sara S. J., Hervé-Minvielle A. (1995). Inhibitory influence of frontal cortex on locus coeruleus neurons. Proc. Natl. Acad. Sci. U.S.A. 92 6032–6036. 10.1073/pnas.92.13.6032
    1. Schiemann J., Puggioni P., Dacre J., Pelko M., Domanski A., vanRossum M. C. W., et al. (2015). Cellular mechanisms underlying behavioral state-dependent bidirectional modulation of motor cortex output. Cell Rep. 11 1319–1330. 10.1016/j.celrep.2015.04.042
    1. Schultz W. (1998). Predictive reward signal of dopamine neurons. J. Neurophysiol. 80 1–27. 10.1152/jn.1998.80.1.1
    1. Schultz W. (2016). Dopamine reward prediction-error signalling: a two-component response. Nat. Rev. Neurosci. 17:183. 10.1038/nrn.2015.26
    1. Schultz W., Dayan P., Montague P. R. (1997). A neural substrate of prediction and reward. Science 275 1593–1599. 10.1126/science.275.5306.1593
    1. Schwarz L. A., Miyamichi K., Gao X. J., Beier K. T., Weissbourd B., Deloach K. E., et al. (2015). Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature 524 88–92. 10.1038/nature14600
    1. Sharma Y., Xu T., Graf W. M., Fobbs A., Sherwood C. C., Hof P. R., et al. (2010). Comparative anatomy of the locus coeruleus in humans and nonhuman primates. J. Comp. Neurol. 518 963–971. 10.1002/cne.22249
    1. Simpson K. L., Waterhouse B. D., Lin R. C. S. (1999). Origin, distribution, and morphology of galaninergic fibers in the rodent trigeminal system. J. Comp. Neurol. 411 524–534. 10.1002/(SICI)1096-9861(19990830)411:3<524::AID-CNE13>;2-X
    1. Spencer R. C., Berridge C. W. (2019). Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants. Neuropsychopharmacology 44 1820–1827. 10.1038/s41386-019-0314-y
    1. Steinmetz N. A., Zatka-Haas P., Carandini M., Harris K. D. (2019). Distributed coding of choice, action and engagement across the mouse brain. Nature 576 266–273. 10.1038/s41586-019-1787-x
    1. Stowell R. D., Sipe G. O., Dawes R. P., Batchelor H. N., Lordy K. A., Whitelaw B. S., et al. (2019). Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nat. Neurosci. 22 1782–1792. 10.1038/s41593-019-0514-0
    1. Swift K. M., Gross B. A., Frazer M. A., Bauer D. S., Clark K. J. D., Vazey E. M., et al. (2018). Abnormal locus coeruleus sleep activity alters sleep signatures of memory consolidation and impairs place cell stability and spatial memory. Curr. Biol. 28 3599–3609. 10.1016/j.cub.2018.09.054
    1. Tabansky I., Liang Y., Frankfurt M., Daniels M. A., Harrigan M., Stern S., et al. (2018). Molecular profiling of reticular gigantocellularis neurons indicates that eNOS modulates environmentally dependent levels of arousal. Proc. Natl. Acad. Sci. U.S.A. 115 E6900–E6909. 10.1073/pnas.1806123115
    1. Tait D. S., Brown V. J., Farovik A., Theobald D. E., Dalley J. W., Robbins T. W. (2007). Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur. J. Neurosci. 25 3719–3724. 10.1111/j.1460-9568.2007.05612.x
    1. Takeuchi T., Duszkiewicz A. J., Sonneborn A., Spooner P. A., Yamasaki M., Watanabe M., et al. (2016). Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537 357–362. 10.1038/nature19325
    1. Tervo D. G. R., Proskurin M., Manakov M., Kabra M., Vollmer A., Branson K., et al. (2014). Behavioral variability through stochastic choice and its gating by anterior cingulate cortex. Cell 159 21–32. 10.1016/j.cell.2014.08.037
    1. Tillage R. P., Sciolino N. R., Plummer N. W., Lustberg D., Liles L. C., Hsiang M., et al. (2020). Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors. Brain Struct. Funct. 225 785–803. 10.1007/s00429-020-02035-4
    1. Totah N. K., Neves R. M., Panzeri S., Logothetis N. K., Eschenko O. (2018). The locus coeruleus is a complex and differentiated neuromodulatory system. Neuron 99 1055–1068.e6. 10.1016/j.neuron.2018.07.037
    1. Uematsu A., Tan B. Z., Ycu E. A., Cuevas J. S., Koivumaa J., Junyent F., et al. (2017). Modular organization of the brainstem noradrenaline system coordinates opposing learning states. Nat. Neurosci. 20 1602–1611. 10.1038/nn.4642
    1. Urai A. E., Braun A., Donner T. H. (2017). Pupil-linked arousal is driven by decision uncertainty and alters serial choice bias. Nat. Commun. 8:14637. 10.1038/ncomms14637
    1. Usher M., Cohen J. D., Servan-Schreiber D., Rajkowski J., Aston-Jones G. (1999). The role of locus coeruleus in the regulation of cognitive performance. Science 283 549–554. 10.1126/science.283.5401.549
    1. Valentino R. J., Van Bockstaele E. (2008). Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur. J. Pharmacol. 583 194–203. 10.1016/j.ejphar.2007.11.062
    1. Vankov A., Hervé−Minvielle A., Sara S. J. (1995). Response to novelty and its rapid habituation in locus coeruleus neurons of the freely exploring rat. Eur. J. Neurosci. 7 1180–1187. 10.1111/j.1460-9568.1995.tb01108.x
    1. Varazzani C., San-Galli A., Gilardeau S., Bouret S. (2015). Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys. J. Neurosci. 35 7866–7877. 10.1523/JNEUROSCI.0454-15.2015
    1. Wagatsuma A., Okuyama T., Sun C., Smith L. M., Abe K., Tonegawa S. (2017). Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context. Proc. Natl. Acad. Sci. U.S.A. 115 E310–E316. 10.1073/pnas.1714082115
    1. Weinshenker D. (2008). Functional consequences of locus coeruleus degeneration in alzheimers disease. Curr. Alzheimer Res. 5 342–345. 10.2174/156720508784533286
    1. Xu Y. L., Reinscheid R. K., Huitron-Resendiz S., Clark S. D., Wang Z., Lin S. H., et al. (2004). Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43 487–497. 10.1016/j.neuron.2004.08.005
    1. Yerkes R. M., Dodson J. D. (1908). The relation of strength of stimulus to rapidity of habit-formation. J. Comp. Neurol. Psychol. 18 459–482. 10.1002/cne.920180503
    1. Young W. S., III, Kuhar M. J. (1980). Noradrenergic alpha 1 and alpha 2 receptors: light microscopic autoradiographic localization. Proc. Natl. Acad. Sci. U.S.A. 77 1696–1700.
    1. Yu A. J., Dayan P. (2005). Uncertainty, neuromodulation, and attention. Neuron 46 681–692. 10.1016/j.neuron.2005.04.026
    1. Zerbi V., Floriou-Servou A., Markicevic M., Vermeiren Y., Sturman O., Privitera M., et al. (2019). Rapid reconfiguration of the functional connectome after chemogenetic locus coeruleus activation. Neuron 103 702–718. 10.1016/j.neuron.2019.05.034

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