If you’re on the older side and find yourself popping hideously awake in the middle of the night or far-too-early morn, here’s your line for the next time it happens: “Oh, that darned ventrolateral preoptic nucleus of mine! How I miss my old galanin!”
Researchers have just reported in the journal Brain that they’ve found a group of neurons — in the aforementioned nucleus – that function as a kind of “sleep switch,” and whose degeneration over the years is looking very much like the cause of age-related sleep loss. It’s also looking pivotal in the insomnia that often causes nocturnal wandering in people with Alzheimer’s disease.
“This is the first time that anyone has ever been able to show in humans that there is a distinct group of nerve cells in the brain that’s critical for allowing you to sleep,” said the paper’s senior author, Dr. Clifford Saper, chair of neurology at Beth Israel Deaconess Medical Center and professor of neurology at Harvard Medical School.
You may well be wondering exhaustedly how soon this insight — based on the post-mortem analysis of 45 human brains — will lead to better sleeping pills for older folks. I asked Dr. Saper that, too. No promises with timeframes at this point, but he does see the prospect for better-targeted sleeping pills for seniors, with fewer side effects like Ambien’s balance-related problems.
Our conversation, lightly edited:
Can this group of neurons actually explain the lion’s share of sleep problems that older people and people with Alzheimer’s disease have?
It really can. Let me give you a little background. We discovered this cell group in the brains of rats in 1996. We found that there’s a group of of nerve cells in a part of the brain called the hypothalamus that fire when animals are asleep. And we later found that if you eliminate those nerve cells, that animals lose up to 50 percent of all their sleep time, and the remaining sleep is fragmented. They can’t sleep for long bouts at a time; they keep waking up all the time.
At that time, we weren’t sure whether this would be the same in other species. So we looked at the brains of half a dozen other species — of mice and cats and monkeys — and we found that all of them have this cell group and that the cells were active during sleep in all of them. In every species we looked at, this same cell group had a particular neurotransmitter in it, called galanin.
I’ve never heard of that neurotransmitter before…
Galanin is a peptide, It’s a small string of amino acids that is pretty well known, and it’s found in neurons in a number of places in the brain, but this particular spot in the brain, in all of the species we looked at, the cells that were sleep-active always had galanin in them.
We found a group in the same spot in the human brain, and we proposed that this might in fact be that cell group, and it might actually be important in keeping people asleep. And in fact, there were already some papers that had been done at that time looking at that cell group in human brains and showing that it degenerated with age.
Does it degenerate more than the rest of the brain?
It does. It degenerates more than other cell groups in the hypothalamus that are nearby.
Do we know why?
No, it’s really not known why this happens. The best work on this was done by a Dutch group, led by Dick Swaab, and he found that young people have about 30,000 nerve cells in this cell group, and by the time you reach 70 you have about 15,000 left. So you lose half of them between young adulthood and older adulthood.
In any case, we proposed that this might be the mechanism of sleep problems in older people, but we had no way to prove it at the time. And I was discussing that when I was giving a seminar at Rush Medical College in Chicago, and the person who heads their Memory and Aging Project, Dr. David Bennett, who’s a co-author on the paper, said, ‘We may have a way to solve that problem.’ They had a cohort of people, 1000 people, in a long term NIH study, and all of these people get annual evaluations.
The Memory and Aging Project is looking for triggers for developing Alzheimer’s and Parkinson’s disease. And one of the things the subjects do is wear a wrist bracelet every year for 10 days that measures their arm movement. It’s called an actigram. It gathers data on people’s movements, and it’s possible, by looking at the movement patterns, to determine what period of time they’re actually asleep. When they’re asleep, they don’t move their arm for periods of several minutes or more. It works.
So after validating that, we then analyzed the actigraphy from a large number of people, and then we looked at their brains after they died. Everyone in the study donates their brain when they die. And again, they’re mainly looking for Alzheimer’s and Parkinson’s disease, but we could look at the ventrolateral preoptic nucleus, this little cell group, and determine if the galanin cells were intact.
The brains were predominantly from people in their mid-80s, And what we found is that by the time you reach 85, you have even fewer of these cells left; you have in the typical range of 5,000 to 10,000 of these, though some people had even fewer than that. And then we correlated their sleeping behavior with the number of cells that each individual had.
What we found was that the people who had the fewest cells had the most difficulty sleeping. And the second finding was that the people who had the very fewest cells, the very tiniest numbers and the worst sleep, had Alzheimer’s disease — which surprised us. We didn’t expect that. But even the normal people who don’t have Alzheimer’s disease, their sleep behavior is still predicted by the number of cells left in this part of the brain.
So that’s powerful enough to make you say this isn’t just correlation, we think this is causation?
That’s the key. I think if you just had those data in humans it would be a great correlation but you couldn’t prove much from it. However, because we have the data where we selectively killed those cells in experimental animals and demonstrated the same effect, I think it’s pretty clear that this is very likely to be the cause of the loss of sleep as people age as well.
So what does this mean for drug development?
The tricky part is that we now know that the ventrolateral preoptic nucleus is important for sleep and we know what its neurotransmitters are: they contain galanin and they contain another, inhibitory neurotransmitter called GABA. Most of the drugs we use for sleep now act by mimicking the GABA and turning off the targets of the ventrolateral preoptic nucleus. That’s why they help you fall asleep. The downside of that is that there are GABA receptors in many other parts of the brain, and one part where they’re most prominent is the cerebellum, which is important for balance. So you take older people and give them a drug that inhibits the waking system, and you also cause them to fall down.
So that’s why you have the announcement that you have to cut back on the amount of Ambien you give older people, because it tends to make them fall more. So you’d like to develop drugs that are more specific, and one of the targets might be galanin, and another target might be looking at the specific types of GABA receptors in the particular parts of the brain where the ventrolateral preoptic nucleus causes sleep. It turns out there’s many, many different classes of GABA receptors and it’s possible to develop drugs that activate some but not others.
Has that work begun?
There are various groups in the pharmaceutical industry that are doing this kind of work. Unfortunately, there is no drug yet that makes this distinction.
But in the coming years, a drug could be developed that targets the right GABA or galanin?
There might be, and there’s another alternative, which is that what the ventrolateral preoptic neurons do is they turn off the waking systems, so you could have a drug that specifically targets the waking system. So for example, there’s a new drug that Merck has just released which is an orexin antagonist. And one of the things the ventrolateral preoptic neurons do is they inhibit the orexin neurons.
So all in all, this offers a bit more hope to all the seniors waking up at 3 and 4 a.m.?
It does. This is an incredibly common problem. And for people who have Alzheimer’s disease it’s even worse, because this is often what sends them into a nursing home. They can’t sleep at night and get up and wander. The caregivers can’t keep up with it after a while, and they have to put them into a nursing home.