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.
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West, R. L. An application of prefrontal cortex function theory to cognitive aging. Psychol. Bull. 120, 272–292 (1996)
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)
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)
Prakash, R. S. et al. Age-related differences in the involvement of the prefrontal cortex in attentional control. Brain Cogn. 71, 328–335 (2009)
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)
Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995)
Robbins, T. W. & Arnsten, A. F. The neuropsychopharmacology of fronto-executive function: monoaminergic modulation. Annu. Rev. Neurosci. 32, 267–287 (2009)
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)
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)
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)
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)
Burke, S. N. & Barnes, C. A. Neural plasticity in the ageing brain. Nature Rev. Neurosci. 7, 30–40 (2006)
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)
Davis, H. P. et al. Lexical priming deficits as a function of age. Behav. Neurosci. 104, 288–297 (1990)
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)
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)
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)
Rapp, P. R. & Amaral, D. G. Evidence for task-dependent memory dysfunction in the aged monkey. J. Neurosci. 9, 3568–3576 (1989)
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)
Rypma, B. & D’Esposito, M. Isolating the neural mechanisms of age-related changes in human working memory. Nature Neurosci. 3, 509–515 (2000)
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)
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)
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)
Downs, J. L. et al. Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol. Aging 28, 1286–1295 (2007)
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)
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)
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)
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)
Peters, A. et al. Neurobiological bases of age-related cognitive decline in the rhesus monkey. J. Neuropathol. Exp. Neurol. 55, 861–874 (1996)
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)
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.
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.
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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
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