Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuronal basis of age-related working memory decline

Nature volume 476, pages 210–213 (2011)Cite this article

Subjects

Abstract

Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction1,2,3,4. The PFC guides behaviour and thought using working memory5, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation6. This fragile process is highly dependent on the neurochemical environment7. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels8,9. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Age-related changes in the PFC networks that subserve working memory.
Figure 2: Age-dependent decline in the spatially tuned, persistent firing of dorsolateral PFC DELAY neurons.
Figure 3: Firing rates of dorsolateral PFC CUE cells remain stable in aged monkeys.
Figure 4: Iontophoresis of compounds that inhibit cAMP–PKA signalling, or block HCN or KCNQ channel signalling, strengthens delay-related firing in aged PFC DELAY neurons.

References

  1. West, R. L. An application of prefrontal cortex function theory to cognitive aging. Psychol. Bull. 120, 272–292 (1996)

    Article  CAS  Google Scholar 

  2. Cabeza, R., Anderson, N. D., Houle, S., Mangels, J. A. & Nyberg, L. Age-related differences in neural activity during item and temporal-order memory retrieval: a positron emission tomography study. J. Cogn. Neurosci. 12, 197–206 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Prakash, R. S. et al. Age-related differences in the involvement of the prefrontal cortex in attentional control. Brain Cogn. 71, 328–335 (2009)

    Article  Google Scholar 

  5. Goldman-Rakic, P. S. in Handbook of Physiology, The Nervous System, Higher Functions of the Brain Vol. 5 (ed. Plum, F. ) 373–417 (American Physiological Society, 1987)

    Google Scholar 

  6. Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995)

    Article  CAS  Google Scholar 

  7. Robbins, T. W. & Arnsten, A. F. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu. Rev. Neurosci. 32, 267–287 (2009)

    Article  CAS  Google Scholar 

  8. Wang, M. et al. α2A-adrenoceptor stimulation strengthens working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129, 397–410 (2007)

    Article  CAS  Google Scholar 

  9. Arnsten, A. F. T., Paspalas, C. D., Gamo, N. J., Yang, Y. & Wang, M. Dynamic network connectivity: a new form of neuroplasticity. Trends Cogn. Sci. 14, 365–375 (2010)

    Article  Google Scholar 

  10. Bowles, R. P. & Salthouse, T. A. Assessing the age-related effects of proactive interference on working memory tasks using the Rasch model. Psychol. Aging 18, 608–615 (2003)

    Article  Google Scholar 

  11. Royall, D. R., Palmer, R., Chiodo, L. K. & Polk, M. J. Normal rates of cognitive change in successful aging: the freedom house study. J. Int. Neuropsychol. Soc. 11, 899–909 (2005)

    Article  Google Scholar 

  12. Burke, S. N. & Barnes, C. A. Neural plasticity in the ageing brain. Nature Rev. Neurosci. 7, 30–40 (2006)

    Article  CAS  Google Scholar 

  13. Cappell, K. A., Gmeindl, L. & Reuter-Lorenz, P. A. Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load. Cortex 46, 462–473 (2010)

    Article  Google Scholar 

  14. Davis, H. P. et al. Lexical priming deficits as a function of age. Behav. Neurosci. 104, 288–297 (1990)

    Article  CAS  Google Scholar 

  15. Bucur, B. & Madden, D. J. Effects of adult age and blood pressure on executive function and speed of processing. Exp. Aging Res. 36, 153–168 (2010)

    Article  Google Scholar 

  16. Sisodia, S. S., Martin, L. J., Walker, L. C., Borchelt, D. R. & Price, D. L. Cellular and molecular biology of Alzheimer’s disease and animal models. Neuroimaging Clin. N. Am. 5, 59–68 (1995)

    CAS  PubMed  Google Scholar 

  17. Moore, T. L., Killiany, R. J., Herndon, J. G., Rosene, D. L. & Moss, M. B. Executive system dysfunction occurs as early as middle-age in the rhesus monkey. Neurobiol. Aging 27, 1484–1493 (2006)

    Article  Google Scholar 

  18. Rapp, P. R. & Amaral, D. G. Evidence for task-dependent memory dysfunction in the aged monkey. J. Neurosci. 9, 3568–3576 (1989)

    Article  CAS  Google Scholar 

  19. Herndon, J. G., Moss, M. B., Rosene, D. L. & Killiany, R. J. Patterns of cognitive decline in aged rhesus monkeys. Behav. Brain Res. 87, 25–34 (1997)

    Article  CAS  Google Scholar 

  20. Rypma, B. & D’Esposito, M. Isolating the neural mechanisms of age-related changes in human working memory. Nature Neurosci. 3, 509–515 (2000)

    Article  CAS  Google Scholar 

  21. George, M. S., Abbott, L. F. & Siegelbaum, S. A. Hyperpolarization-activated HCN channels inhibit subthreshold EPSPs through voltage-dependent interacations with M-type K+ channels. Nature Neurosci. 12, 577–584 (2009)

    Article  CAS  Google Scholar 

  22. Ramos, B. et al. Dysregulation of protein kinase A signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40, 835–845 (2003)

    Article  CAS  Google Scholar 

  23. 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  ADS  CAS  Google Scholar 

  24. Downs, J. L. et al. Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol. Aging 28, 1286–1295 (2007)

    Article  CAS  Google Scholar 

  25. Schoenbaum, G., Setlow, B., Saddoris, M. P. & Gallagher, M. Encoding changes in orbitofrontal cortex in reversal-impaired aged rats. J. Neurophysiol. 95, 1509–1517 (2006)

    Article  Google Scholar 

  26. Luebke, J. I. & Chang, Y. M. Effects of aging on the electrophysiological properties of layer 5 pyramidal cells in the monkey prefrontal cortex. Neuroscience 150, 556–562 (2007)

    Article  CAS  Google Scholar 

  27. Luebke, J., Barbas, H. & Peters, A. Effects of normal aging on prefrontal area 46 in the rhesus monkey. Brain Res. Rev. 62, 212–232 (2010)

    Article  Google Scholar 

  28. Alexander, G. E. et al. Age-related regional network of magnetic resonance imaging gray matter in the rhesus macaque. J. Neurosci. 28, 2710–2718 (2008)

    Article  CAS  Google Scholar 

  29. Peters, A. et al. Neurobiological bases of age-related cognitive decline in the rhesus monkey. J. Neuropathol. Exp. Neurol. 55, 861–874 (1996)

    Article  CAS  Google Scholar 

  30. Dumitriu, D. et al. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J. Neurosci. 30, 7507–7515 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by PHS grant PO1AG030004 from the National Institute on Aging. The authors would like to thank J. Thomas, L. Ciavarella, S. Johnson, B. Brunson and M. Horn for their assistance in making this work possible.

Author information

Authors and Affiliations

  1. Department of Neurobiology, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Min Wang, Nao J. Gamo, Yang Yang, Lu E. Jin, Xiao-Jing Wang, Mark Laubach, James A. Mazer, Daeyeol Lee & Amy F. T. Arnsten

  2. The John B. Pierce Laboratory, New Haven, 06510, Connecticut, USA

    Mark Laubach

Authors
  1. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nao J. Gamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lu E. Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Laubach
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James A. Mazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daeyeol Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Amy F. T. Arnsten
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.W. and X.-J.W., J.A.M., D.L. and A.F.T.A. designed the experiments. M.W. carried out all the physiology experiments, with the help of Y.Y., N.J.G., L.E.J. and J.A.M. Data analyses were performed by M.W., D.L., J.A.M. and M.L. Computational modelling was performed by X.-J.W. All authors participated in the writing of the paper.

Corresponding author

Correspondence to Amy F. T. Arnsten.

Ethics declarations

Competing interests

A.F.T.A. and Yale University receive royalties from Shire Pharmaceuticals from the sales of extended release guanfacine (Intuniv) for the treatment of pediatric ADHD and related disorders (royalties are not received for sales of immediate release guanfacine which is approved for use in adults). A.F.T.A. consults and engages in teaching for Shire, and receives research funding from Shire for the study of catecholamine mechanisms in prefrontal cortex.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-7 with legends, Supplementary Table 1, a Supplementary Discussion and additional references. (PDF 653 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, M., Gamo, N., Yang, Y. et al. Neuronal basis of age-related working memory decline. Nature 476, 210–213 (2011). https://doi.org/10.1038/nature10243

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10243

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing