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Neuronal basis of age-related working memory decline

2011; Nature Portfolio; Volume: 476; Issue: 7359 Linguagem: Inglês

10.1038/nature10243

1476-4687

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

Neuroscience and Neuropharmacology Research

Normal ageing results in the decline of higher cognitive functions, such as working memory and the ability to concentrate. A connection between the neurochemical environment and neuronal function in the prefrontal cortex (PFC) has been proposed as a key factor modulating these declines. Recordings from PFC neurons in young, middle-aged and older monkeys during a learning task reveal a significant decline in persistent firing in the aged PFC neurons that are responsible for maintaining the signal in working memory during a delay following a cue. This firing level can be rescued by restoring an optimal neurochemical environment, present at younger ages, through inhibition of cyclic AMP signalling and closure of the potassium channels that weaken network connectivity. These findings suggest potential therapeutic targets for cognitive enhancers in humans. 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.