Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Working Memory  — Age-Related Decline



Nature 476, 210–213  (11 August 2011)

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

Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

The John B. Pierce Laboratory, New Haven, Connecticut 06510, USA


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.


Executive and working memory functions decline early in the normal ageing process, beginning in middle age. Thus, cognitive changes with advancing age may be costly, forcing retirement from demanding careers and jeopardizing the ability to live independently in an increasingly complex society. Ageing monkeys provide an ideal model to reveal the neurobiology of normal ageing, as they have a highly developed PFC, but are not subject to age-related dementias. Thus, one can be certain that cognitive changes are the result of normal ageing and not incipient Alzheimer’s disease. Like humans, monkeys begin to develop deficits in executive function as early as middle age. Both aged monkeys and humans are impaired on working memory tasks that require constant updating of the contents of memory, bringing to mind information from longer-term stores (for example, where did I leave my car keys this time?), or keeping in mind a recent event (for example, remembering a new phone number).

In primates, spatial working memory depends on the highly evolved dorsolateral PFC. Spatial working memory performance relies on networks of pyramidal neurons that interconnect at dendritic spines, and excite each other to keep information ‘in mind’, that is, generating persistent spiking activity over a delay period in a working memory task. This ability to maintain information that is no longer in the environment is a fundamental process needed for abstract thought and flexible responding. Intracellular signalling pathways modulate the physiological strength of these recurrent, excitatory PFC network connections. Recent data show that increased cAMP signalling weakens network connectivity by opening potassium channels, whereas inhibiting cAMP signalling and/or closing these channels strengthens connectivity and cognitive ability. Specifically, cAMP signalling seems to weaken persistent firing and impair working memory by increasing the open state of HCN (hyperpolarization-activated cyclic nucleotide-gated) channels that are localized on spines where networks interconnect. Recent data indicate that HCN channels may also gate synaptic inputs through interactions with KCNQ channels, whose open state is increased by cAMP-activating protein kinase A (PKA). Studies indicate that cAMP signalling is disinhibited in the aged PFC. Noradrenergic α2A receptor inhibition of cAMP may be reduced from loss of α2A receptors in the aged PFC and decreased excitation of noradrenergic neurons.

The results data indicate that reductions in memory-related firing rate do not arise from generalized changes with advancing age affecting all neurons but, rather, are especially evident in recurrent circuits that must maintain firing in the absence of ‘bottom-up’ sensory stimulation.

It is important to identify which changes in the ageing brain contribute to reduced firing during the delay period. There are many brain alterations associated with advancing age, including decreased PFC grey matter volume, focal changes in white matter and dendritic spine loss, all of which correlate with cognitive decline. Importantly, spine loss is especially prominent in layer III—the layer where the recurrent excitatory networks reside—and thin-type spines are the most vulnerable in the aged PFC. Immunoelectron microscopy indicates that thin spines have the greatest concentration of cAMP–HCN-channel signalling proteins, indicating that disinhibition of cAMP signalling with advancing age may weaken thin spines in particular. Thus, we tested whether inhibition of cAMP signalling in the PFC could partially restore the working-memory-related firing of aged neurons, or whether reductions in firing were irreversible owing to immutable architectural changes in the aged brain. Drugs were applied near the recorded neurons using iontophoresis, whereby a small electrical current is applied to extrude charged molecules from glass pipettes attached to the recording electrode. Only a minute amount of drug was released, sufficient to alter the firing of nearby neurons, without altering behavioural performance.

The current study revealed a physiological basis for age-related working memory decline in the primate brain, with a reduction of memory-related firing beginning in middle age and worsening with advancing age. This marked change in network physiology may render higher cortical circuits especially vulnerable to neurodegenerative processes such as Alzheimer’s disease. However, these studies also uncovered more hopeful data showing that restitution of the proper neurochemical environment can partially restore physiological integrity. These data establish that cognitive changes with advancing age are malleable, and that there is potential to restore at least some cognitive abilities in the elderly. Maintaining strong PFC physiology into advanced age will be an important advantage in an increasingly complex, ageing society.

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