Neuronal basis of age-related working memory decline

Abstract

Many of the cognitive deficits of normal aging (forgetfulness, distractibility, inflexibility, and impaired executive functions) involve prefrontal cortical (PFC) dysfunction1–4. The PFC guides behavior and thought using working memory5, 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 cAMP signaling reduces persistent firing by opening HCN and KCNQ potassium channels8,9. It is not known if molecular changes associated with normal aging alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings 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, while 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 signaling, 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.

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

“…More recently, psychological trauma has been identified as a risk factor for AD as well (41). All three of these factors-aging (23,24), head trauma (42), and psychological trauma (43)-increase cAMP-Ca 2+ signaling in PFC, thus providing a coherent explanation for how they all exacerbate the degenerative process.…”

“…It has been appreciated for many years that Ca 2+ signaling is increased in the aging brain (21,22) and that signs of increased cAMP-PKA signaling in aged PFC correlate with reduced neuronal firing and impaired cognition (23,24). However, it has not been known why cAMP-PKA signaling becomes dysregulated with age and whether these changes contribute to vulnerability to degeneration.…”

Aging impairs intermediate-term behavioral memory by disrupting the dorsal paired medial neuron memory trace

“…All error bars indicate SEM. oxidative stress pathway (26), caloric restriction pathway (27), and PKA-cAMP pathway (28)(29)(30) by using principally pharmacological approaches. Our approach used "thermogenetics" delimited to a single neuron in the fly brain.…”

Working Memory: Maintenance, Updating, and the Realization of Intentions

“…Cognitive interventions have shown some promise in modulating dopamine D1 and D2 systems (McNab et al 2009;Bäckman et al 2011; for reviews, see Klingberg 2010;Bäckman and Nyberg 2013). We are currently exploring the potential role of long-term physical interventions in strengthening dopamine and related cognitive functions, and psychopharmacological approaches hold promise in this regard (Wang et al 2011). An important task for future research is to examine further ways of supporting deficient working-memory networks, as this in turn may influence significant aspects of everyday functioning.…”