New research in mice identifies a range of neurons that may be involved in promoting sleep. The findings may soon change therapeutic practices for treating sleep disorders.

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Neurons that express the so-called Lhx6 gene may promote sleep by “switching off” other neurons.

Insomnia affects around 60 million people in the United States every year. It is associated with a variety of health concerns, particularly among the elderly, including cognitive impairment and metabolic syndrome.

As any person who has had a sleepless night will know, trying to “will” yourself to sleep during an episode of insomnia is not just unhelpful, but it might also make matters even worse. But what if there was a “switch” in our brain that we could activate when we want to fall asleep?

A new study may have found such a “switch” in a type of neuron. Having surveyed the existing research, scientists from the Johns Hopkins University School of Medicine in Baltimore, MD, realized that while a significant amount of work has been done on neurons that promote wakefulness, little research has focused on neurons that promote sleep.

So, the scientists – led by Seth Blackshaw, Ph.D., a professor of neuroscience at the Johns Hopkins University School of Medicine – set out to examine the role of brain cells that express a gene called “Lhx6.”

The reason why the researchers decided to examine this particular gene is that it plays a crucial role in forming neurons that inhibit the activity of other neurons. Previous research led by Prof. Blackshaw observed the role of this gene in mice.

He explains the motivation for the study’s focus, saying, “We know cells in other regions of the brain use Lhx6 and that the gene is vital for these areas to develop properly. For example, disrupting Lhx6 expression can result in many diseases, including severe epilepsy.”

So the researchers wondered, what if neurons that express the Lhx6 gene promote sleep by “switching off” other neurons that keep us awake?

The first author of the study is Kai Liu, a graduate student in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine, and the findings were published in the journal Nature.

Liu and team created a mouse model wherein they used “designer receptors exclusively activated by designer drugs” to analyze whether activating Lhx6-expressing neurons would promote or inhibit sleep.

They used the drug clozapine N-oxide to activate Lhx6-expressing neurons, as well as the Fos protein and viral tracing techniques to study the behavior of these neurons.

Liu and team found that mice slept more and spent more time in both random eye movement (REM) and non-REM sleep during the 12 hours after they received the neuron-activating drug injection. These effects were at their highest between 2 and 8 hours after receiving the drug.

Roughly put, non-REM sleep comprises a stage of deep, restful sleep, whereas REM sleep is considered to be lighter and the sleep phase during which most of our dreaming occurs.

The fact that these [Lhx6-expressing neurons] promote both non-REM and REM sleep distinguishes them from other sleep-regulating cells. They present a new target for treating a broad range of sleep disorders.”

Prof. Seth Blackshaw

Additionally, the researchers observed this activity in a brain area wherein Lhx6-expressing neurons had not been identified before: a region in the hypothalamus called zona incerta.

“Because the hypothalamus is an ancient system that was relatively well-conserved in evolution from fish to humans, understanding its genetics and chemistry in mice should advance our knowledge of what happens in people’s brains,” explains Prof. Blackshaw.

Previous research identified neurons that promote wakefulness by secreting hypocretin, which is a neuropeptide. So in the new study, the researchers also wanted to see whether Lhx6-expressing neurons inhibited these hypocretin-secreting neurons.

By blocking the action of hypocretin using designer drugs and activating Lhx6-expressing neurons, the researchers found that the mice continued to have increased REM sleep, but not non-REM sleep.

“This shows that Lhx6 inhibits not only hypocretin-producing cells, but also other types of wake-promoting cells,” explains Liu.