Neuronal basis of age-related working memory decline


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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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.


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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.

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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.

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Correspondence to Amy F. T. Arnsten.

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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.

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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).

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