Neuronal basis of age-related working memory decline

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

Research output: Contribution to journalLetter

Abstract

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.

Original languageEnglish (US)
Pages (from-to)210-213
Number of pages4
JournalNature
Volume476
Issue number7359
DOIs
StatePublished - Aug 11 2011

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    Wang, M., Gamo, N. J., Yang, Y., Jin, L. E., Wang, X. J., Laubach, M., Mazer, J. A., Lee, D., & Arnsten, A. F. T. (2011). Neuronal basis of age-related working memory decline. Nature, 476(7359), 210-213. https://doi.org/10.1038/nature10243