title: Neuronal basis of age-related working memory decline.
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.
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Nao J
authors.initials: NJ
authors.lastname: Gamo
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Lu E
authors.initials: LE
authors.lastname: Jin
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Laubach
authors.forename: James A
authors.initials: JA
authors.lastname: Mazer
authors.forename: Daeyeol
authors.initials: D
authors.lastname: Lee
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000375:Aging / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D000818:Animals; D024803:Biomedical Enhancement; D003463:Cues; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D016316:Guanfacine / Q000494:pharmacology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008253:Macaca mulatta / Q000502:physiology*; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008959:Models, Neurological; D009434:Neural Pathways / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology* / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D018341:Receptors, Adrenergic, alpha-2; D016316:Guanfacine; D000242:Cyclic AMP