Yale Bulletin and Calendar

March 23, 2007|Volume 35, Number 22

NIH grant will advance research
on neurons' role in narcolepsy

Yale School of Medicine researchers have received a $1.5 million grant from the National Institutes of Health (NIH) to study neurons that play a major role in narcolepsy.

Narcolepsy is a neurodegenerative disease characterized by daytime sleepiness. The NIH grant will further Yale research into narcolepsy and other disorders linked to neurons that produce the peptide hypocretin.

"The activity of these hypocretin cells is important for enhancing cognitive arousal and resisting sleep, and they may also play a role in anxiety and body weight regulation," says principal investigator Anthony van den Pol, professor of neurosurgery.

Neurons send out long fibers, or axons, to other nerve cells and release either an inhibitor or excitatory neurotransmitter onto their target cells, explains van den Pol. A small number of these neurons make and secrete the transmitter hypocretin.

Hypocretin neurons actually make two neurotransmitters -- hypocretin and dynorphin. The results of van den Pol's recent work, published in the Journal of Neuroscience, shows that these two transmitters, or peptides, have actions that oppose each other. Hypocretin increases the excitability of other nerve cells, whereas dynorphin inhibits the activity.

Van den Pol and first author, Ying Li, an associate research scientist, wondered what cellular value opposing neurotransmitters might have. They found that different target neurons in the brain show different responses to co-stimulation by the two peptides.

They came to this conclusion by using whole cell patch clamp recording, in which an ultra-thin glass pipette, like a very small straw, is used to record the electrical activity caused by movement of ions through channels in single nerve cells.

Van den Pol says that these neurotransmitters had different effects on different cell types. One target, MCH neurons, were excited by hypocretin but inhibited by dynorphin.

"This might suggest that the two neurotransmitters would simply cancel the actions of each other," van den Pol says. "But, interestingly, in the continuing presence of both neurotransmitters, the inhibitory MCH cell response to dynorphin rapidly declined, whereas the excitatory response to hypocretin persisted." Therefore, he adds, low levels of release of both transmitters might favor inhibition, whereas high levels of release might swing the tide over to excitation and increase cognitive arousal.

However, on another target, NPY neurons, hypocretin directly excited the cells, but dynorphin had little direct effect. Rather, dynorphin contributed to increased nerve cell activity by reducing the release of inhibitory neurotransmitters onto the NPY cells. In this case, the transmitters act synergistically to excite the NPY cell.

Under the NIH grant, van den Pol and colleagues will study the effects of both naturally occurring neuroactive compounds, as well as man-made drugs, to determine how they influence the hypocretin cells and, ultimately, cognitive arousal.

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