(Image caption:
General anesthesia drugs were shown to induce unconsciousness by
activating a tiny cluster of cells at the base of the brain called the
supraoptic nucleus (shown in red), while the rest of the brain remains
in a mostly inactive state (shown in blue))

General Anesthesia Hijacks Sleep Circuitry to Knock You Out

The discovery of general anesthesia 170 years
ago was a medical miracle, enabling millions of patients to undergo
invasive, life-saving surgeries without pain. Yet despite decades of
research, scientists still don’t understand why general anesthesia
works.

Now scientists think they have discovered part of the answer. In a study published online in Neuron,
a Duke University team found that several different general anesthesia
drugs knock you out by hijacking the neural circuitry that makes you
fall asleep.

The researchers traced this neural circuitry
to a tiny cluster of cells at the base of the brain responsible for
churning out hormones to regulate bodily functions, mood, and sleep. The
finding is one of the first to suggest a role for hormones in
maintaining the state of general anesthesia, and provides valuable
insights for generating newer drugs that could put people to sleep with
fewer side effects.

Ever since the first patient went under
general anesthesia in 1846, scientists have been trying to figure out
exactly how it works. The prevailing theory has been that many of these
drugs tamp down the brain’s normal activities, resulting in the
inability to move or feel pain. Similar theories revolved around sleep,
the sister state to general anesthesia. However, research over the last
decade has shown that sleep is a more active process than previously
recognized, with entire sets of neurons clocking in to work while you
catch your Z’s.

Fan Wang, Ph.D., a professor of neurobiology
at the Duke University School of Medicine, and Li-Feng Jiang-Xie, a
graduate student in her laboratory, wondered whether the predominant
view of general anesthesia was also one-sided. “Perhaps rather than
simply inhibiting neurons, anesthetics could also activate certain
neurons in the brain,” said Jiang-Xie.

To test their new theory, Jiang-Xie and
Luping Yin, Ph.D., a postdoctoral fellow in the Wang lab, put mice under
general anesthesia with several different but commonly used drugs. Then
they used molecular markers to track down the neurons that were
commonly activated by the anesthetics. They found a cluster of actively
firing neurons buried in a tiny brain region called the supraoptic
nucleus, which is known to have leggy projections that release large
amounts of hormones like vasopressin directly into the bloodstream.

“Most of the anesthesia-activated cells were a
kind of hybrid cell that connects the nervous system and the endocrine
system,” said Jiang-Xie. “That took us by surprise and led us into
unexplored territory for understanding the neural pathways of general
anesthesia.”

Next, the researchers tapped a sophisticated
technique developed in the Wang lab to turn on or off this specialized
group of cells with chemicals or light. When they switched on the cells
in mice, the animals stopped moving and fell into a deep slumber called
slow wave sleep, typically associated with unconsciousness.

Then the research team killed off this group of cells. The mice continued to move around, unable to fall asleep.

Finally, the researchers performed similar
experiments on mice under general anesthesia. They found that
artificially pre-activating the neuroendocrine cells made the mice stay
under general anesthesia for longer periods of time. Conversely, when
they silenced these cells, the mice woke up from anesthesia more easily.

This study also revealed a previously unexpected role of the brain’s hormone-secreting cells in promoting deep sleep.

“Many people, particularly those with
Alzheimer’s disease, have difficulty falling to sleep, yet current
medications have troublesome side effects,” said Yin. “If we can find
ways to manipulate this neural circuitry, perhaps by targeting hormones
or small peptides, then it could lead to the development of better
sleeping pills.”



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