Neuronal basis of age-related working memory decline
Open accessAbstract
Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour and thought using working memory, 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 stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Marked loss of PFC persistent firing in aged monkeys is partially restored by inhibiting cAMP signaling or blocking HCN or KCNQ channels.
“The marked loss of PFC persistent firing in aged monkeys is also partially restored by inhibiting cAMP signaling or blocking HCN or KCNQ channels 238.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [238]
In the healthy aging brain, there is a decline in neuronal activity, a loss of synaptic connections, and a decrease in synaptic function.
“In the healthy aging brain, there is a decline in neuronal activity, a loss of synaptic connections, and a decrease in synaptic function (Wang et al., 2011).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Wang et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cellular basis of working memory
Goldman-Rakic, P. S. (1995) · Neuron · doi:10.1016/0896-6273(95)90304-6 · Cited by 2,663 · see citing works
An application of prefrontal cortex function theory to cognitive aging.
West, R. L. (1996) · Psychological Bulletin · doi:10.1037/0033-2909.120.2.272 · Cited by 2,032 · see citing works
Neural plasticity in the ageing brain
Burke, S. N., & Barnes, C. A. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1809 · Cited by 1,600 · see citing works
The Neuropsychopharmacology of Fronto-Executive Function: Monoaminergic Modulation
Robbins, T. W., & Arnsten, A. F. T. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135535 · Cited by 957 · see citing works
Self-citationTop-down suppression deficit underlies working memory impairment in normal aging
Gazzaley, A., Cooney, J. W., Rissman, J., & D'Esposito, M. (2005) · Nature Neuroscience · doi:10.1038/nn1543 · Cited by 934 · see citing works
Wang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., Duque, A., Vijayraghavan, S., Brennan, A., Dudley, A., Nou, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.03.015 · Cited by 672 · see citing works
Self-citationIsolating the neural mechanisms of age-related changes in human working memory
Rypma, B., & D’Esposito, M. (2000) · Nature Neuroscience · doi:10.1038/74889 · Cited by 549 · see citing works
Dumitriu, D., Hao, J., Hara, Y., Kaufmann, J., Janssen, W. G. M., Lou, W., Rapp, P. R., & Morrison, J. H. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.6410-09.2010 · Cited by 439 · see citing works
Cappell, K. A., Gmeindl, L., & Reuter‐Lorenz, P. A. (2009) · Cortex · doi:10.1016/j.cortex.2009.11.009 · Cited by 374 · see citing works
Neurobiological Bases of Age-Related Cognitive Decline in the Rhesus Monkey
Peters, A., Rosene, D. L., Moss, M. B., Kemper, T. L., Abraham, C. R., Tigges, J., & Albert, M. (1996) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199608000-00001 · Cited by 344 · see citing works
Patterns of cognitive decline in aged rhesus monkeys
Herndon, J. G., Moss, M. B., Rosene, D. L., & Killiany, R. (1997) · Behavioural Brain Research · doi:10.1016/s0166-4328(96)02256-5 · Cited by 290 · see citing works
Cabeza, R. E. L., Anderson, N. D., Houle, S., Mangels, J. A., & Nyberg, L. H. (2000) · Journal of Cognitive Neuroscience · doi:10.1162/089892900561832 · Cited by 281 · see citing works
Evidence for task-dependent memory dysfunction in the aged monkey
Rapp, P. R., & Amaral, D. (1989) · Journal of Neuroscience · doi:10.1523/jneurosci.09-10-03568.1989 · Cited by 277 · see citing works
Dysregulation of Protein Kinase A Signaling in the Aged Prefrontal Cortex
Ramos, B. P., Birnbaum, S. G., Lindenmayer, I., Newton, S. S., Duman, R. S., & Arnsten, A. F. T. (2003) · Neuron · doi:10.1016/s0896-6273(03)00694-9 · Cited by 218 · see citing works
Self-citationGeorge, M. S., Abbott, L. F., & Siegelbaum, S. A. (2009) · Nature Neuroscience · doi:10.1038/nn.2307 · Cited by 187 · see citing works
Dynamic network connectivity: a new form of neuroplasticity
Arnsten, A. F. T., Paspalas, C. D., Gamo, N. J., Yang, Y., & Wang, M. (2010) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2010.05.003 · Cited by 160 · see citing works
Self-citationExecutive system dysfunction occurs as early as middle-age in the rhesus monkey
Moore, T. L., Killiany, R., Herndon, J. G., Rosene, D. L., & Moss, M. B. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.08.004 · Cited by 141 · see citing works
Lexical priming deficits as a function of age.
Davis, H. P., Cohen, A., Gandy, M., Colombo, P. J., VanDusseldorp, G., Simolke, N., & Romano, J. (1990) · Behavioral Neuroscience · doi:10.1037/0735-7044.104.2.288 · Cited by 134 · see citing works
CELLULAR AND MOLECULAR BIOLOGY OF ALZHEIMER'S DISEASE AND ANIMAL MODELS
Price, D. L., & Sisodia, S. S. (1994) · Annual Review of Medicine · doi:10.1146/annurev.med.45.1.435 · Cited by 132 · see citing works
Age-related differences in the involvement of the prefrontal cortex in attentional control
Prakash, R. S., Erickson, K. I., Colcombe, S. J., Kim, J., Voss, M. W., & Kramer, A. F. (2009) · Brain and Cognition · doi:10.1016/j.bandc.2009.07.005 · Cited by 118 · see citing works
Normal rates of cognitive change in successful aging: The Freedom House Study
ROYALL, D. R., PALMER, R., CHIODO, L. K., & POLK, M. J. (2005) · Journal of the International Neuropsychological Society · doi:10.1017/s135561770505109x · Cited by 118 · see citing works
Bowles, R. P., & Salthouse, T. A. (2003) · Psychology and Aging · doi:10.1037/0882-7974.18.3.608 · Cited by 102 · see citing works
Age-Related Regional Network of Magnetic Resonance Imaging Gray Matter in the Rhesus Macaque
Alexander, G. E., Chen, K., Aschenbrenner, M., Merkley, T. L., Santerre-Lemmon, L. E., Shamy, J. L., Skaggs, W. E., Buonocore, M. H., Rapp, P. R., & Barnes, C. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1852-07.2008 · Cited by 101 · see citing works
Effects of normal aging on prefrontal area 46 in the rhesus monkey
Luebke, J. I., Barbas, H., & Peters, A. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.12.002 · Cited by 98 · see citing works
Encoding Changes in Orbitofrontal Cortex in Reversal-Impaired Aged Rats
Schoenbaum, G. M., Setlow, B., Saddoris, M. P., & Gallagher, M. (2005) · Journal of Neurophysiology · doi:10.1152/jn.01052.2005 · Cited by 83 · see citing works
Moore, T. L., Schettler, S. P., Killiany, R., Herndon, J. G., Luebke, J. I., Moss, M. B., & Rosene, D. L. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.12.003 · Cited by 79 · see citing works
Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque
Downs, J. L., Dunn, M. R., Borók, E., Shanabrough, M., Horváth, T. L., Kohama, S. G., & Urbanski, H. F. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.05.025 · Cited by 77 · see citing works
Effects of Adult Age and Blood Pressure on Executive Function and Speed of Processing
Bucur, B., & Madden, D. J. (2010) · Experimental Aging Research · doi:10.1080/03610731003613482 · Cited by 76 · see citing works
Luebke, J. I., & Chang, Y. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.09.042 · Cited by 47 · see citing works
CELLULAR AND MOLECULAR BIOLOGY OF ALZHEIMER'S DISEASE AND ANIMAL MODELS
Sisodia, S. S., Martin, L. J., Walker, L. C., Borchelt, D., & Price, D. L. (1995) · Neuroimaging Clinics of North America · doi:10.1016/s1052-5149(25)00276-x · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course
McEwen, B. S., & Morrison, J. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.028 · Cited by 1,079 · see citing works
The ageing cortical synapse: hallmarks and implications for cognitive decline
Morrison, J. H., & Baxter, M. G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3200 · Cited by 965 · see citing works
The aging astrocyte transcriptome from multiple regions of the mouse brain.
Boisvert, M. M., Erikson, G. A., Shokhirev, M. N., & Allen, N. J. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.039 · Cited by 702 · see citing works
Novel electrode technologies for neural recordings
Hong, G., & Lieber, C. M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0140-6 · Cited by 695 · see citing works
Moffitt, T. E., Houts, R., Asherson, P., Belsky, D. W., Corcoran, D. L., Hammerle, M., Harrington, H., Hogan, S., Meier, M. H., Polanczyk, G. V., et al. (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.14101266 · Cited by 618 · see citing works
Dendritic spine pathology in schizophrenia
Glausier, J. R., & Lewis, D. A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.044 · Cited by 581 · see citing works
The neuroscience of working memory capacity and training
Constantinidis, C., & Klingberg, T. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.43 · Cited by 533 · see citing works
Arnsten, A. F. T., Wang, M. J., & Paspalas, C. D. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.038 · Cited by 538 · see citing works
Self-citationHuman cognitive aging: <i>Corriger la fortune?</i>
Lindenberger, U. (2014) · Science · doi:10.1126/science.1254403 · Cited by 414 · see citing works
Yan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
“The marked loss of PFC persistent fi ring in aged monkeys is also partially restored by inhibiting cAMP signaling or blocking HCN or KCNQ channels [238].”
BackgroundYi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., & Südhof, T. C. (2016) · Science · doi:10.1126/science.aaf2669 · Cited by 313 · see citing works
Dendritic spine changes associated with normal aging
Dickstein, D. L., Weaver, C. M., Luebke, J. I., & Hof, P. R. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.09.077 · Cited by 289 · see citing works
Moynihan, J. A., Chapman, B. P., Klorman, R., Krasner, M. S., Duberstein, P. R., Brown, K. W., & Talbot, N. L. (2013) · Neuropsychobiology · doi:10.1159/000350949 · Cited by 210 · see citing works
Wei, Z., Wang, X.-J., & Wang, D.-H. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0735-12.2012 · Cited by 163 · see citing works
Self-citationChronic Stress Weakens Connectivity in the Prefrontal Cortex: Architectural and Molecular Changes.
Woo, E., Sansing, L. H., Arnsten, A. F. T., & Datta, D. (2021) · Chronic Stress · doi:10.1177/24705470211029254 · Cited by 159 · see citing works
Self-citationMesh electronics: a new paradigm for tissue-like brain probes
Hong, G., Yang, X., Zhou, T., & Lieber, C. M. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.11.007 · Cited by 159 · see citing works
Driesen, N. R., McCarthy, G., Bhagwagar, Z., Bloch, M. H., Calhoun, V. D., D'Souza, D. C., Gueorguieva, R., He, G., Leung, H.-C., Ramani, R., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.170 · Cited by 148 · see citing works
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex
Carlyle, B. C., Nairn, A. C., Wang, M., Yang, Y., Jin, L. E., Simen, A. A., Ramos, B. P., Bordner, K. A., Craft, G. E., Davies, P., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322360111 · Cited by 139 · see citing works
Self-citationImportance of the nicotinic acetylcholine receptor system in the prefrontal cortex
Wallace, T. L., & Bertrand, D. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.04.001 · Cited by 133 · see citing works
Deficit of cognitive inhibition in depressed elderly: a neurocognitive marker of suicidal risk
Richard-Devantoy, S., Jollant, F., Kefi, Z., Turecki, G., J.P.Olié, Annweiler, C., Beauchet, O., & Le Gall, D. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.03.006 · Cited by 128 · see citing works
Oligomeric Aβ in the monkey brain impacts synaptic integrity and induces accelerated cortical aging
Beckman, D., Ott, S., Donis-Cox, K., Janssen, W. G., Bliss-Moreau, E., Rudebeck, P. H., Baxter, M. G., & Morrison, J. H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902301116 · Cited by 111 · see citing works
Longevity factor klotho enhances cognition in aged nonhuman primates
Castner, S. A., Gupta, S., Wang, D., Moreno, A. J., Park, C., Chen, C., Poon, Y., Groen, A., Greenberg, K., David, N., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00441-x · Cited by 114 · see citing works
Psychostimulants and motivated behavior: Arousal and cognition
Berridge, C. W., & Arnsten, A. F. T. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.11.005 · Cited by 104 · see citing works
Self-citationGalvin, V. C., Yang, S. T., Paspalas, C. D., Yang, Y., Jin, L. E., Datta, D., Morozov, Y. M., Lightbourne, T. C., Lowet, A. S., Rakic, P., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.030 · Cited by 79 · see citing works
Self-citationArnsten, A. F. T., Datta, D., Leslie, S., Yang, S.-T., Wang, M., & Nairn, A. C. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903671116 · Cited by 74 · see citing works
Self-citationDatta, D., Leslie, S. N., Morozov, Y. M., Duque, A., Rakic, P., van Dyck, C. H., Nairn, A. C., & Arnsten, A. F. T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1683-1 · Cited by 76 · see citing works
Self-citationArnsten, A. F. T. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107327 · Cited by 75 · see citing works
“, 2014), and that regulation through α2A-AR is especially helpful in restoring PFC neuronal firing (Wang et al., 2011).”
Self-citationNissim, N. R., O’Shea, A., Indahlastari, A., Telles, R., Richards, L., Porges, E., Cohen, R., & Woods, A. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00051 · Cited by 63 · see citing works
HCN Channel Targets for Novel Antidepressant Treatment
Ku, S. M., & Han, M.-H. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0538-7 · Cited by 54 · see citing works
Vijayraghavan, S., Major, A. J., & Everling, S. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.027 · Cited by 51 · see citing works
Ramcharitar, J., Albrecht, S., Afonso, V. M., Kaushal, V., Bennett, D. A., & LeBlanc, A. C. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182a0a39f · Cited by 47 · see citing works
Effects of α-2A adrenergic receptor agonist on time and risk preference in primates
Kim, S., Bobeica, I., Gamo, N. J., Arnsten, A. F. T., & Lee, D. (2012) · Psychopharmacology · doi:10.1007/s00213-011-2520-0 · Cited by 47 · see citing works
Self-citationAcute stress and working memory: the role of sex and cognitive stress appraisal
Zandara, M., Garcia-Lluch, M., Pulopulos, M. M., Hidalgo, V., Villada, C., & Salvador, A. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.06.022 · Cited by 44 · see citing works
Kv7 Channels and Excitability Disorders
Jones, F., Gamper, N., & Gao, H. (2021) · Handbook of Experimental Pharmacology · doi:10.1007/164_2021_457 · Cited by 38 · see citing works
Role of KCNQ potassium channels in stress-induced deficit of working memory
Arnsten, A. F. T., Jin, L. E., Gamo, N. J., Ramos, B., Paspalas, C. D., Morozov, Y. M., Kata, A., Bamford, N. S., Yeckel, M. F., Kaczmarek, L. K., et al. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100187 · Cited by 27 · see citing works
Self-citationChang, W., Weaver, C., Medalla, M., Moore, T., & Luebke, J. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.09.012 · Cited by 20 · see citing works
Functional alterations of the prefrontal circuit underlying cognitive aging in mice
Chong, H. R., Ranjbar-Slamloo, Y., Ho, M. Z. H., Ouyang, X., & Kamigaki, T. (2023) · Nature Communications · doi:10.1038/s41467-023-43142-0 · Cited by 19 · see citing works
- Authors
- Wang, M., Gamo, N. J., Yang, Y., Jin, L. E., Wang, X.-J., Laubach, M., Mazer, J. A., Lee, D., & Arnsten, A. F. T.
- Affiliations
- Yale University (US)
- Corresponding author
- Arnsten, Amy F. T.
- Venue
- Nature
- Published
- 2011-07-27
- Volume
- 476
- Issue
- 7359
- Pages
- 210-213
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3193794
- OpenAlex
- W2043955468
- Cited by
- 485
- References
- 30
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 28 · 2023: 39 · 2022: 20 · 2021: 47 · 2020: 29 · 2019: 24 · 2018: 32 · 2017: 34 · 2016: 32 · 2015: 31 · 2014: 22 · 2013: 47 · 2012: 40
- FWCI
- 18.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (P01AG030004)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- age-related cognitive decline, working memory, prefrontal cortex, cAMP signaling, HCN channels, KCNQ potassium channels, dorsolateral prefrontal cortex, aged monkeys, network connectivity, nootropic drugs
- MeSH terms
- Action Potentials, Cyclic AMP, Aging, Animals, Cues, Humans, Macaca mulatta, Male, Memory, Short-Term, Models, Neurological, Neural Pathways, Time Factors, Potassium Channels, Signal Transduction, Guanfacine, Prefrontal Cortex, Receptors, Adrenergic, alpha-2, Biomedical Enhancement, Potassium Channel Blockers, KCNQ Potassium Channels, Cyclic Nucleotide-Gated Cation Channels, Adrenergic alpha-2 Receptor Agonists, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
