While we’re asleep at night, our brain is busy doing maintenance. The glymphatic system–the brain’s waste disposal mechanism–flushes away excess cerebrospinal fluid containing harmful proteins that otherwise build up slowly in the brain. Accumulation of these proteins has been associated with increased risk of conditions like Alzheimer’s Disease. In a new paper published January 8 in Cell, scientists are getting closer to uncovering how the system knows when to engage: the “switch” for activating the system is the brain’s neurotransmitter norepinephrine.
The glymphatic system was discovered by Danish neuroscientist and one of the paper’s authors Maiken Nedergaard in 2012, who gave its name to reflect both its resemblance to the better-known lymphatic system and its reliance on the brain’s glial cells. She tells Popular Science that the system has been studied extensively over the last decade, and that its operation is critical to a healthy brain: “There are now approximately 2,000 published articles on the glymphatic system, many of which focus on clinical applications. These studies collectively highlight that aging and nearly all neurological diseases are associated with a reduction in glymphatic flow.”
Every minute or so during non-rapid eye movement (NREM) sleep, the brain releases a wave of norepinephrine, a hormone that is one of the brain’s primary neurotransmitters. Norepinephrine is a potent vasoconstrictor, causing blood vessels to narrow, and each wave causes a contraction in the arteries that carry blood to the brain. The arteries then dilate slowly until the arrival of the next norepinephrine wave.
Nedergaard explains that this rhythmic series of contractions and dilations creates a pumping action: “It is the oscillatory constriction-dilations that drive glymphatic flow.” The oscillating waves of norepinephrine that create these arterial contractions are critical to the glymphatic system’s operation.
As one of the brain’s primary neurotransmitters, norepinephrine has many functions, and there are several classes of drug that work by modifying the rate at which it is released and reuptaken. Examples include antidepressants—especially selective norepinephrine reuptake inhibitors (SNRIs)—and beta blockers, which block one of the receptors to which norepinephrine binds.
There are also other drugs that aren’t aimed specifically at the norepinephrine system but affect it regardless. Unfortunately, sleep medications fall into the latter category, and the study examines how one common medication—Zolpidem, also known as Ambien—affects the activation and operation of the glymphatic system.
Researchers compared two groups of mice, one of which was given Zolpidem. The team found that in the Zolpidem-dosed mice, the release of norepinephrine—and, as a result, the operation of the glymphatic system—was noticeably suppressed. Peak norepinephrine levels in the brains of the Zolpidem mice were some 50% lower than in the control group, and arterial constrictions were also less pronounced.
The study concludes that in mice, at least, Zolpidem “interferes with normal sleep architecture and suppresses glymphatic flow.” Nedergaard says that the picture is likely to be the same for other sleep medications, because ultimately they all work by suppressing neural activity across the brain. This includes the neurons that release norepinephrine. This suggests that sleeping medications have the unintended consequence of interfering with the brain’s way of flushing away dangerous waste.
This problem may also extend to other medications. Nedergaard says that SNRIs, for example, also appear to inhibit the oscillation mechanism: her lab conducted another study in which the SNRI desipramine was administered to mice, and “basically eliminated … oscillations.”
This illustrates one important point about the system: the brain doesn’t just keep releasing norepinephrine forever. If the overall level of norepinephrine is high, and the neurons that release it get a signal to release more, the amount they release will decrease. In other words, the brain tries to maintain a balance.
By inhibiting the reabsorption of norepinephrine, SNRIs result in an overall elevation of its level in the brain. This means that when the glymphatic system starts to ramp up during sleep, it has less “room” to operate, and the waves of norepinephrine released on activation of the glymphatic system are relatively small. And, as Nedgergaard emphasizes, “It is the oscillations [in norepinephrine levels] that matter.”
There’s still a lot to learn about the glymphatic system, but that a priority should be ensuring that its operation is not inhibited by the drugs we take to help us sleep. She suggests future research on this topic could look into sleep aids that have a more sophisticated mechanism of action than just a blanket suppression of neuronal activity. A better approach, she says, would be finding ways to allow norepinephrine oscillations, helping people to sleep but also “promot[ing] restorative sleep viewed from a glymphatic point of view.”
