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Arousal increases neural gain via the locus coeruleus–noradrenaline system in younger adults but not in older adults

Nature Human Behaviour volume 2, pages 356–366 (2018)Cite this article

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Abstract

In younger adults, arousal amplifies attentional focus to the most salient or goal-relevant information while suppressing other information. A computational model of how the locus coeruleus–noradrenaline system can implement this increased selectivity under arousal and a functional magnetic resonance imaging (fMRI) study comparing how arousal affects younger and older adults’ processing indicate that the amplification of salient stimuli and the suppression of non-salient stimuli are separate processes, with ageing affecting suppression without affecting amplification under arousal. In the fMRI study, arousal increased processing of salient stimuli and decreased processing of non-salient stimuli for younger adults. By contrast, for older adults, arousal increased processing of both low- and high-salience stimuli, generally increasing excitatory responses to visual stimuli. Older adults also showed a decline in locus coeruleus functional connectivity with frontoparietal networks that coordinate attentional selectivity. Thus, among older adults, arousal increases the potential for distraction from non-salient stimuli.

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Fig. 1: A graphical depiction of the proposed mechanisms of the GANE model.
Fig. 2: Order of events during MRI session and during each experimental trial.
Fig. 3: Place area activity during the spatial detection task.
Fig. 4: Computational modelling.
Fig. 5: Age differences in the effects of arousal on frontoparietal activity and how the frontoparietal effects relate to pupil dilation.
Fig. 6: Functional connectivity seed regions and results.
Fig. 7: Comparisons of younger and older adults' functional connectivity patterns among the LC, PPA and frontoparietal network regions.

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  PubMed  Google Scholar 

  3. Mather, M. & Sutherland, M. R. Arousal-biased competition in perception and memory. Perspect. Psychol. Sci. 6, 114–133 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lee, T. H., Sakaki, M., Cheng, R., Velasco, R. & Mather, M. Emotional arousal amplifies the effects of biased competition in the brain. Soc. Cogn. Affect. Neurosci. 9, 2067–2077 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sutherland, M. R. & Mather, M. Negative arousal amplifies the effects of saliency in short-term memory. Emotion 12, 1367–1372 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Womelsdorf, T. & Everling, S. Long-range attention networks: circuit motifs underlying endogenously controlled stimulus selection. Trends Neurosci. 38, 682–700 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, S. et al. Long-range and local circuits for top-down modulation of visual cortex processing. Science 345, 660–665 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Corbetta, M. & Shulman, G. L. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 3, 201–215 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Guedj, C., Meunier, D., Meunier, M. & Hadj-Bouziane, F. Could LC-NE-dependent adjustment of neural gain drive functional brain network reorganization?. Neural Plast. 2017, 4328015 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hernaus, D., Casales Santa, M. M., Offermann, J. S. & Van Amelsvoort, T. Noradrenaline transporter blockade increases fronto-parietal functional connectivity relevant for working memory. Eur. Neuropsychopharmacol. 27, 399–410 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Strange, B. A. & Dolan, R. J. β-Adrenergic modulation of oddball responses in humans. Behav. Brain Funct. 3, 29 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bigham, M. H. & Lidow, M. S. Adrenergic and serotonergic receptors in aged monkey neocortex. Neurobiol. Aging 16, 91–104 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Moore, T. L. et al. Cognitive impairment in aged rhesus monkeys associated with monoamine receptors in the prefrontal cortex. Behav. Brain Res. 160, 208–221 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Berchtold, N. C. et al. Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease. Neurobiol. Aging 34, 1653–1661 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Erraji-Benchekroun, L. et al. Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol. Psychiatry 57, 549–558 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Rozycka, A. & Liguz‐Lecznar, M. The space where aging acts: focus on the GABAergic synapse. Aging Cell 16, 634–643 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kann, O., Papageorgiou, I. E. & Draguhn, A. Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J. Cereb. Blood Flow. Metab. 34, 1270–1282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hua, T., Kao, C., Sun, Q., Li, X. & Zhou, Y. Decreased proportion of GABA neurons accompanies age-related degradation of neuronal function in cat striate cortex. Brain Res. Bull. 75, 119–125 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Spiegel, A. M., Koh, M. T., Vogt, N. M., Rapp, P. R. & Gallagher, M. Hilar interneuron vulnerability distinguishes aged rats with memory impairment. J. Comp. Neurol. 521, 3508–3523 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Braak, H. & Braak, E. Ratio of pyramidal cells versus non-pyramidal cells in the human frontal isocortex and changes in ratio with ageing and Alzheimer’s disease. Prog. Brain Res. 70, 185–212 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Stanley, E. M., Fadel, J. R. & Mott, D. D. Interneuron loss reduces dendritic inhibition and GABA release in hippocampus of aged rats. Neurobiol. Aging 33, 431.e1–431.e13 (2012).

    Article  CAS  Google Scholar 

  23. Avelar-Pereira, B., Bäckman, L., Wåhlin, A., Nyberg, L. & Salami, A. Age-related differences in dynamic interactions among default mode, frontoparietal control, and dorsal attention networks during resting-state and interference resolution. Front. Aging Neurosci. 9, 152 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. DuPre, E. & Spreng, R. N. Structural covariance networks across the life span, from 6 to 94 years of age. Netw. Neurosci. 1, 302–323 (2017).

    Article  Google Scholar 

  25. Grady, C., Sarraf, S., Saverino, C. & Campbell, K. Age differences in the functional interactions among the default, frontoparietal control, and dorsal attention networks. Neurobiol. Aging 41, 159–172 (2016).

    Article  PubMed  Google Scholar 

  26. Mitchell, K. J., Ankudowich, E., Durbin, K. A., Greene, E. J. & Johnson, M. K. Age-related differences in agenda-driven monitoring of format and task information. Neuropsychologia 51, 2427–2441 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Nashiro, K., Sakaki, M., Braskie, M. N. & Mather, M. Resting-state networks associated with cognitive processing show more age-related decline than those associated with emotional processing. Neurobiol. Aging 54, 152–162 (2017).

    Article  PubMed  Google Scholar 

  28. Siman-Tov, T. et al. Early age-related functional connectivity decline in high-order cognitive networks. Front. Aging Neurosci. 8, 330 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Downing, P. E., Chan, A. W. Y., Peelen, M. V., Dodds, C. M. & Kanwisher, N. Domain specificity in visual cortex. Cereb. Cortex 16, 1453–1461 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Slaney, T. R., Mabrouk, O. S., Porter-Stransky, K. A., Aragona, B. J. & Kennedy, R. T. Chemical gradients within brain extracellular space measured using low flow push–pull perfusion sampling in vivo. ACS Chem. Neurosci. 4, 321–329 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Harley, C. W., Lalies, M. D. & Nutt, D. J. Estimating the synaptic concentration of norepinephrine in dentate gyrus which produces β-receptor mediated long-lasting potentiation in vivo using microdialysis and intracerebroventricular norepinephrine. Brain Res. 710, 293–298 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ferrero, J. J. et al. β-Adrenergic receptors activate exchange protein directly activated by cAMP (Epac), translocate Munc13-1, and enhance the Rab3A–Rim1α interaction to potentiate glutamate release at cerebrocortical nerve terminals. J. Biol. Chem. 288, 31370–31385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nai, Q., Dong, H.-W., Hayar, A., Linster, C. & Ennis, M. Noradrenergic regulation of GABAergic inhibition of main olfactory bulb mitral cells varies as a function of concentration and receptor subtype. J. Neurophysiol. 101, 2472–2484 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Amara, S. G. & Kuhar, M. J. Neurotransmitter transporters: recent progress. Annu. Rev. Neurosci. 16, 73–93 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Nee, D. E., Wager, T. D. & Jonides, J. Interference resolution: insights from a meta-analysis of neuroimaging tasks. Cogn. Affect. Behav. Neurosci. 7, 1–17 (2007).

    Article  PubMed  Google Scholar 

  37. Scolari, M., Seidl-Rathkopf, K. N. & Kastner, S. Functions of the human frontoparietal attention network: evidence from neuroimaging. Curr. Opin. Behav. Sci. 1, 32–39 (2015).

    Article  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  Google Scholar 

  39. 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).

    Article  CAS  PubMed  Google Scholar 

  40. Napadow, V., Dhond, R., Kennedy, D., Hui, K. K. & Makris, N. Automated brainstem co-registration (ABC) for MRI. Neuroimage 32, 1113–1119 (2006).

    Article  PubMed  Google Scholar 

  41. Laird, A. R. et al. Behavioral interpretations of intrinsic connectivity networks. J. Cogn. Neurosci. 23, 4022–4037 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhang, S., Hu, S., Chao, H. H. & Li, C.-S. R. Resting-state functional connectivity of the locus coeruleus in humans: in comparison with the ventral tegmental area/substantia nigra pars compacta and the effects of age. Cereb. Cortex 26, 3413–3427 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gannon, M. & Wang, Q. Complex noradrenergic dysfunction in Alzheimer’s disease: low norepinephrine input is not always to blame. Brain Res. https://doi.org/10.1016/j.brainres.2018.01.001 (2018).

  44. Healey, M. K., Hasher, L. & Campbell, K. L. The role of suppression in resolving interference: evidence for an age-related deficit. Psychol. Aging 28, 721–728 (2013).

    Article  PubMed  Google Scholar 

  45. Gazzaley, A., Cooney, J. W., Rissman, J. & D’Esposito, M. Top-down suppression deficit underlies working memory impairment in normal aging. Nat. Neurosci. 8, 1298–1300 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Mitchell, K. J., Johnson, M. R., Higgins, J. A. & Johnson, M. K. Age differences in brain activity during perceptual versus reflective attention. Neuroreport 21, 293–297 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Smith, S. M. et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23, S208–S219 (2004).

    Article  PubMed  Google Scholar 

  48. Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17, 825–841 (2002).

    Article  PubMed  Google Scholar 

  49. Smith, S. M. Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143–155 (2002).

    Article  PubMed  Google Scholar 

  50. Beckmann, C. F. & Smith, S. M. Probabilistic independent component analysis for functional magnetic resonance imaging. IEEE Trans. Med. Imaging 23, 137–152 (2004).

    Article  PubMed  Google Scholar 

  51. Tohka, J. et al. Automatic independent component labeling for artifact removal in fMRI. Neuroimage 39, 1227–1245 (2008).

    Article  PubMed  Google Scholar 

  52. Brady, T. F., Konkle, T., Alvarez, G. A. & Oliva, A. Visual long-term memory has a massive storage capacity for object details. Proc. Natl Acad. Sci. USA 105, 14325–14329 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Brainard, D. H. The psychophysics toolbox. Spat. Vis. 10, 433–436 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Pelli, D. G. The VideoToolbox software for visual psychophysics: transforming numbers into movies. Spat. Vis. 10, 437–442 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Epstein, R. & Kanwisher, N. A cortical representation of the local visual environment. Nature 392, 598–601 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Epstein, R. The cortical basis of visual scene processing. Vis. Cogn. 12, 954–978 (2005).

    Article  Google Scholar 

  57. Grill-Spector, K. & Malach, R. fMR-adaptation: a tool for studying the functional properties of human cortical neurons. Acta Psychol. 107, 293–321 (2001).

    Article  CAS  Google Scholar 

  58. Erez, Y. & Yovel, G. Clutter modulates the representation of target objects in the human occipitotemporal cortex. J. Cogn. Neurosci. 26, 490–500 (2014).

    Article  PubMed  Google Scholar 

  59. Altmann, C. F., Deubelius, A. & Kourtzi, Z. Shape saliency modulates contextual processing in the human lateral occipital complex. J. Cogn. Neurosci. 16, 794–804 (2004).

    Article  PubMed  Google Scholar 

  60. Gazzaley, A. et al. Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing. Cereb. Cortex 17, I125–I135 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Mumford, J. A., Turner, B. O., Ashby, F. G. & Poldrack, R. A. Deconvolving BOLD activation in event-related designs for multivoxel pattern classification analyses. Neuroimage 59, 2636–2643 (2012).

    Article  PubMed  Google Scholar 

  62. Okubo, Y. et al. Imaging extrasynaptic glutamate dynamics in the brain. Proc. Natl Acad. Sci. USA 107, 6526–6531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Keren, N. I., Lozar, C. T., Harris, K. C., Morgan, P. S. & Eckert, M. A. In vivo mapping of the human locus coeruleus. Neuroimage 47, 1261–1267 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institute on Aging RO1AG025340 awarded to M.M., JSPS KAKENHI 16H03750 and 15K21062 awarded to T.U., and JSPS KAKENHI 16H05959, 16KT0002 and 16H02053 and European Commission CIG618600 awarded to M.S. We thank C. Cho for assistance with Figs. 1 and 7. The funders had no role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Psychology, University of Southern California, Los Angeles, CA, USA

    Tae-Ho Lee, Steven G. Greening & Mara Mather

  2. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Tae-Ho Lee, Steven G. Greening, Allison Ponzio & Mara Mather

  3. Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Tae-Ho Lee

  4. Department of Psychology, Louisiana State University, Baton Rouge, LA, USA

    Steven G. Greening

  5. School of Human Sciences, Takachiho University, Suginami, Tokyo, Japan

    Taiji Ueno

  6. Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA

    David Clewett & Mara Mather

  7. Department of Psychology, New York University, New York, NY, USA

    David Clewett

  8. School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK

    Michiko Sakaki

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Contributions

T.-H.L. and M.M. designed the study. T.-H.L., S.G.-G. and A.P. acquired the data. Data were analysed by T.-H.L. with S.G.-G., D.C. and M.M. Modelling was conducted by T.U. and M.S. All the authors contributed to the preparation of the manuscript.

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Correspondence to Mara Mather.

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Lee, TH., Greening, S.G., Ueno, T. et al. Arousal increases neural gain via the locus coeruleus–noradrenaline system in younger adults but not in older adults. Nat Hum Behav 2, 356–366 (2018). https://doi.org/10.1038/s41562-018-0344-1

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