A study comparing activity in the dorsolateral prefrontal cortex in young, middle-aged and aged macaque monkeys as they performed a spatial working memory task has found that while neurons of the young monkeys maintained a high rate of firing during the task, neurons in older animals showed slower firing rates. The decline began in middle age.

Neuron activity was recorded in a particular area of the dorsolateral prefrontal cortex that is most important for visuospatial working memory. Some neurons only fired when the cue was presented (28 CUE cells), but most were active during the delay period as well as the cue and response periods (273 DELAY neurons). Persistent firing during the delay period is of particular interest, as it is required to maintain information in working memory. Many DELAY neurons increased their activity when the preferred spatial location was being remembered.

While the activity of the CUE cells was unaffected by age, that of DELAY cells was significantly reduced. This was true both of spontaneous activity and task-related activity. Moreover, the reduction was greatest during the cue and delay periods for the preferred direction, meaning that the effect of age was to reduce the ability to distinguish preferred and non-preferred directions.

It appeared that the aging prefrontal cortex was accumulating excessive levels of an important signaling molecule called cAMP. When cAMP was inhibited or cAMP-sensitive ion channels were blocked, firing rates rose to more youthful levels. On the other hand, when cAMP was stimulated, aged neurons reduced their activity even more.

The findings are consistent with rat research that has found two of the agents used — guanfacine and Rp-cAMPS — can improve working memory in aged rats. Guanfacine is a medication that is already approved for treating hypertension in adults and prefrontal deficits in children. A clinical trial testing guanfacine's ability to improve working memory and executive functions in elderly subjects who do not have dementia is now taking place.