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Rise of the planet of the aged

August 17, 2011

Picture from Wikipedia - Cerebral cortex (brain)

In the new movie ‘Rise of the planet of the apes’, actor James Franco plays a scientist trying to cure debilitating conditions developed in old-age such as Alzheimer’s. He ends up developing a virus which can cause mutations in apes enabling them to regenerate brain cells (neurons). Instead of finding a cure for Alzheimer’s though, it ends up catapulting apes above humans as the dominant species on the planet. Researchers at Yale University working with monkeys have now identified the neuro-physiological basis for decline of working memory with old age.

The pre-frontal cortex (PFC) is a part of the brain in primates that guides behaviour and thought using working memory, enabling us to remember things like ‘where are the car keys’ or ‘what was that phone number’. A network of neurons in the PFC start ‘firing’ (generating voltage spikes) when a ‘cue’ (some external stimulus or information) is received, and the firing persists for some time (many seconds) even after the cue is removed. This persistent firing is responsible for our working memory.

The Yale scientists trained monkeys of three age groups (young, middle-aged and old) to perform a spatial working memory task where they were shown a ‘cue’ at one out of eight locations for half a second, and then asked to remember the exact location after another 2.5 seconds, in order to obtain a reward (juice). They observed that the persistent firing rate of PFC neurons, during the delay period after the cue, decreased with increasing age.

PFC neurons have a high concentration of cAMP (cyclic adenosine monophosphate), a “messenger” molecule derived from ATP (adenosine triphosphate, the energy unit of the cell) used for intracellular signal transduction. An important function of cAMP is to activate proteins that act as channels for the flow of ions like potassium into and out of the cell. The authors suspected that this cAMP signaling and opening of ion channels might be interfering with the firing of PFC neurons, since it was known that cAMP activity is amplified with advancing age. To test this hypothesis, they administered drugs to the old monkeys in the vicinity of the PFC neurons which either inhibited cAMP activity or blocked the ion channels. Remarkably, in both cases they observed that the persistent firing rate of neurons, during the delay period after the cue, was almost restored to the same level as that of the young monkeys.

One of the drugs, guanfacine, is now being tested in elderly humans with cognitive defects related to the PFC. The potential to restore cognitive abilities of our rapidly ageing population could result in a paradigm shift in our view of human society.

 

Wang, M., Gamo, N., Yang, Y., Jin, L., Wang, X., Laubach, M., Mazer, J., Lee, D., & Arnsten, A. (2011). Neuronal basis of age-related working memory decline Nature, 476 (7359), 210-213 DOI: 10.1038/nature10243

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