Have you ever found that after a late night of studying, or maybe a bender of a weekend, your brain just doesn’t seem to be running at full capacity?
Good news: it isn’t all in your head. Well, technically it is. Recent research has found that inhibiting an enzyme involved in cognitive functioning and memory reverses these effects.
Sleep deprivation results in increased levels of an enzyme called phosphodiesterase 4 (PDE4). PDE4 is responsible for the breakdown of cyclic adenosine monophosphate (cAMP), a molecule required for various cognitive functions. Increased levels of cAMP in the hippocampus are associated with improved memory and learning.
An analogy to help understand this enzymatic process is to think of cAMP as a flower, and PDE4 as a herbivore, such as a rabbit. If there is an increase in the rabbit population, the flower population will consequently become depleted and processes that require flowers, such as pollination, will be limited. On the other hand, if the rabbit population was to decrease, this would result in an increase in flowers and the processes they are involved in.
This study was a collaborative effort involving many researchers, including Dr. Ted Abel from the University of Pennsylvania, and neurophysiologist Dr. Min Zhuo from the University of Toronto. Sleep-deprived mice were subjected to a fear test, which measured ability to recognize a dangerous environment to which they’d previously been exposed. In sleep-deprived mice with the PDE4 inhibitor, sleep-deprivation-induced-deficits in cAMP signalling, neuron-to-neuron communication and hippocampus-dependent memory were improved. Zhuo commented, “[by] reducing phosphodiesterase activity, [we] could actually see that memory was being rescued.”
The study’s findings are pivotal for neuroscience research in the area of sleep disorders, such as insomnia.
People suffering from sleep deprivation—often ensuing from insomnia—are all too familiar with impaired cognitive function. Inhibiting PDE4 provides a mechanism through which impaired memory can be reversed, and thus may become a target for new pharmacological treatments. However, as with all neuromolecular alterations, there are likely unfavourable side effects.
Zhuo is an expert in chronic pain and “memory receptors.” In 1999, he was the co-author of a momentous neuroscience study with Princeton, MIT, and the University of Washington, creating genetically modified mice with improved learning and memory. These smart mice were named Doogie after the television program Doogie Howser, MD.
In later studies, Zhuo determined that Doogie’s intelligence came with a price: enhanced chronic pain. Other studies have also found that Doogie mice experience more instances of emotions such as fear. There is also evidence that the molecular pathway responsible for providing these mice an intellectual boost is associated with heightened addiction, creating yet another unintended side effect.
Although the creation of Doogie was a significant step forward in the ability to manipulate intelligence, the enhancement method was at the genetic level, which is still ethically controversial. More recent studies inhibiting PDE4 use a mechanism more appropriate for societal application.
There are already many prescription drugs on the market that inhibit a different PDE4 isoform that targets sexual performance in addition to brain activity.
Pill popping to enhance cognitive performance is not a new phenomenon. University campuses across the country are stocked with countless students taking drugs such as Ritalin, Adderall, and the most recent addition, Modafinal, as study aids. It is likely that a new pharmacological drug targeting PDE4 will be added to the list in the future.
As a treatment strategy for sleep-deprived individuals such as insomniacs, the ramifications of this research are extremely valuable. These findings have the potential to substantially increase the quality of life for those suffering from a sleeping disorder. The inhibitor may also have a role for people travelling between time zones who experience severe jet lag.
Further studies in the area of PDE4 inhibition are imperative to allow for the targeting of specific systems, while reducing the risk of unintended side effects. Zhuo cautions that “Improvements in memory and learning may come at a price.”
