The authors then deleted two genes that

encode ion-channel proteins in the retro­

Neuroscience
splenial cortex. The first gene encodes a

An altered state of
channel activated by the neurotransmitter
molecule glutamate. The second encodes
hyperpolarization-activated cyclic nucleo­

consciousness illuminated tide-gated 1 (HCN1), a channel activated

by cations that is sometimes called a pace-
maker, because of its ability to produce
rhythmic activity in the heart and neurons.
Ken Solt & Oluwaseun Akeju
Vesuna et al. found that the ketamine-induced
The rhythmic activity of a single layer of neurons has rhythm was reduced in mice lacking either
now been shown to cause dissociation — an experience gene. However, only the HCN1 channel was
needed for ketamine to elicit dissociation-like
involving a feeling of disconnection from the behaviours.
surrounding world. See p.87 Do these findings translate to humans?
Vesuna and colleagues recorded electri-
cal activity from several brain regions in a
The state of dissociation is commonly cause dissociation. They made use of mice person with epilepsy, who had previously
described as feeling detached from reality or in which layer-5 cells were modified to simul- had electrodes implanted in their cranium
having an ‘out of body’ experience. This altered taneously express two ion-channel proteins to locate seizure activity. The individual
state of consciousness is often reported that are sensitive to light. The first, channel- experi­enced dissociation before the onset of
by people who have psychiatric disorders rhodopsin-2, elicits neuronal excitation in seizures. The authors found that this disso-
arising from devastating trauma or abuse. It response to blue light. The second, eNpHR3.0, ciation correlated with a 3-Hz rhythm in the
is also evoked by a class of anaesthetic drug, silences neurons in response to yellow light. deep postero­medial cortex — a human brain
and can occur in epilepsy. The neurological Illuminating the cells with alternating blue region analogous to the mouse retrosplenial
basis of dissociation has been a mystery, but and yellow light to induce an artificial 2-Hz cortex. When the team electrically stimu-
on page 87, Vesuna et al.1 describe a localized rhythm produced behaviours indicative of a lated the deep postero­medial cortex during
brain rhythm that underlies this state. Their dissociated state, analogous to those caused a brain-mapping procedure, the person again
findings will have far-reaching implications by ketamine (Fig. 1a). For example, the animals experienced dissociation (Fig. 1b).
for neuroscience. did not jump or rear away from threats and It is premature to draw definitive con-
The authors first recorded brain-wide did not try to escape when suspended by their clusions from a single individual. However,
neuronal activity in mice using a technique tails, but responded normally to pain induced Vesuna and colleagues’ work provides com-
called widefield calcium imaging. They stud- by a hotplate. Although sensation remained pelling evidence that a low-frequency rhythm
ied changes in these brain rhythms in response intact, the blunted responses to threats in the deep posteromedial cortex is an evolu-
to a range of drugs that have sedative, anaes- suggest dissociation from the surrounding tionarily conserved mechanism that underlies
thetic or hallucinogenic properties, including environment. dissociation across species.
three that induce dissociation — ketamine,
phencyclidine (PCP) and dizocilpine (MK801).
a Mouse b Human
Only the dissociative drugs produced
robust oscillations in neuronal activity in a Neural activity Blue-light pulse
brain region called the retrosplenial cortex.
This region is essential for various cognitive
functions, including episodic memory and Yellow-light pulse
navigation2. The oscillations occurred at a
low frequency, of about 1–3 hertz. By contrast, Optogenetic Electrical
non-dissociative drugs such as the anaes- stimulation stimulation
thetic propofol and the hallucinogen lysergic Deep
Retrosplenial posteromedial
acid diethylamide (LSD) did not trigger this cortex cortex
rhythmic retrosplenial activity.
Vesuna et al. examined the active cells in
more detail using a high-resolution approach
called two-photon imaging. This analysis
revealed that the oscillations were restricted Dissociation-like behaviours Dissociation experience
that mimic the effects of ketamine that mimics pre-seizure aura
to cells in layer 5 of the retrosplenial cortex.
The authors then recorded neuronal activ-
Figure 1 | Inducing a dissociative state. Dissociation is an altered state of consciousness in which people feel
ity across multiple brain regions. Normally,
detached from reality. It can be triggered by the drug ketamine, and can occur before a seizure in epilepsy.
other parts of the cortex and subcortex are
a, Optogenetic techniques can modulate neuronal activity in response to light. Vesuna et al.1 modulated
functionally connected to neuronal activity
neurons in a single layer of the retrosplenial cortex — a region inside the mouse brain. The group used blue
in the retrosplenial cortex; however, ketamine light to stimulate activity and yellow light to repress it. This generated low-frequency neuronal oscillations,
caused a disconnect, such that many of these similar to those seen in mice that receive ketamine. The oscillations triggered behaviours indicative of
brain regions no longer communicated with dissociation. b, The authors show that the same oscillations occur in the equivalent brain region (called the
the retrosplenial cortex. deep posteromedial cortex) in a person who has epilepsy, before a seizure. Electrical stimulation of this brain
The researchers next asked whether region triggered the same oscillations and dissociative experience. Together, these experiments indicate that
inducing the retrosplenial rhythm could low-frequency oscillations in a small brain region trigger dissociation across species.

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News & views
Much of the success of Vesuna and col- These analyses will be highly challenging Care and Pain Medicine, Massachusetts
leagues’ study relies on the reversible disso- to perform, because studying deep cortical General Hospital, Boston.
ciative effects of ketamine. At sub­anaesthetic rhythms requires people in whom intracranial e-mail: ksolt@mgh.harvard.edu
doses, this fascinating drug elicits dissocia- electrodes have been implanted. For ethical 1. Vesuna, S. et al. Nature 586, 87–94 (2020).
tion and pain relief (analgesia), and has anti- reasons, only individuals who require elec- 2. Vann, S. D., Aggleton, J. P. & Maguire, E. A. Nature Rev.
depressant and anti-suicidal properties. At trodes for therapeutic purposes can partici- Neurosci. 10, 792–802 (2009).
3. Vlisides, P. E. et al. Br. J. Anaesth. 121, 249–259 (2018).
these doses, electroencephalograms (EEGs, pate in such studies. We owe them a debt of 4. Akeju, O. et al. Clin. Neurophysiol. 127, 2414–2422 (2016).
which detect neuronal activity at the surface of gratitude for allowing us to better understand 5. Melonakos, E. D. et al. Anesthesiology 133, 19–30 (2020).
the brain) show that ketamine broadly damp- the inner workings of the human brain. 6. Hemmings, H. C. Jr et al. Trends Pharmacol. Sci. 40,
464–481 (2019).
ens 8–12-Hz oscillations3. At higher doses 7. Yu, X. et al. Nature Neurosci. 22, 106–119 (2019).
that induce unconsciousness, EEGs reveal a Ken Solt and Oluwaseun Akeju are in the 8. Taylor, N. E. et al. Proc. Natl Acad. Sci. USA 113,
rhythm in the brain’s frontal lobe in humans Department of Anaesthesia, Harvard Medical 12826–12831 (2016).
9. Gitlin, J. et al. Anesthesiology (in the press).
that alternates between low (1–4 Hz) and high School, Boston, Massachusetts 02115, USA,
(27–40 Hz) frequencies4. Given that these and the Department of Anesthesia, Critical This article was published online on 16 September 2020.
changes occur over large areas of the brain’s
surface, it is striking that a small layer of deep
Drug discovery
cells is specifically responsible for dissociation.

Modular synthesis enables

To our knowledge, the oscillations described
by Vesuna et al. have not been reported previ-
ously for ketamine. This is probably because
surface EEG recordings cannot detect localized
rhythms generated deep in the cortex. molecular ju-jitsu
Rapid technological advances are produc-
ing increasingly sophisticated techniques
Daniel J. Blair & Martin D. Burke
to manipulate neural circuits with precision
and high temporal resolution. Vesuna and An ancient resistance mechanism poses a problem when
colleagues’ work exemplifies how these using streptogramin antibiotics. A modular approach to
advances are enabling investigators to probe
the nature of consciousness itself. They are
drug synthesis exploits this same mechanism to generate an
also revolutionizing the science of anaesthe- antibiotic that avoids the emergence of resistance. See p.145
siology5 — allowing investigators to better
understand how anaesthetics produce uncon-
sciousness6, how these mechanisms overlap The development of resistance to antibiotics work synergistically to inhibit bacterial pro-
with natural sleep7, and how people recover by microorganisms is a problem that has been tein synthesis by binding to complementary
consciousness after anaesthesia8. Research billions of years in the making, but we don’t sites in the catalytic centre of the bacterial
into consciousness and anaesthesia overlaps, have as long as that to solve it1,2. One way to ribosome (the molecular machinery that
too, because anaesthetics provide a powerful, speed up the search for solutions is to har- coordinates protein synthesis). Group  A
reliable means of eliciting reversible states of ness human creativity and modern science to strepto­gramins, such as VM2, bind to part of
altered consciousness. Understanding the rationally design resistance-evasive variants the ribosome called the peptidyl transferase
neural mechanisms of these altered states of naturally occurring antibiotic molecules3,4. centre (PTC), and promote the binding of
might lead to fresh approaches to modulate Unfortunately, such molecules often have to group B streptogramins to the adjacent tunnel
consciousness and control pain without the be synthesized from scratch using long, highly region, through which nascent proteins exit.
undesirable side effects of currently availa- customized sequences of reactions that are A key mechanism of bacterial resistance
ble drugs, which include changes in heart rate to this powerful antibiotic ‘one–two punch’
and blood pressure, cessation of breathing, “Replacement of a methyl probably evolved in parallel with the strep-
delirium and nausea. togramins, in the form of acetyltransferase
The complex state of dissociation can be
group with a larger group enzymes of the Vat family (VatA enzymes).
fully described only by humans, who can yielded a compound with These enzymes deactivate group A strepto­
report their experience. For example, a study in potent activity against a gramins by transferring an acetyl group
humans was needed to prove that the dissoci- (–COCH3) to an alcohol group (–OH) attached
ative and analgesic properties of ketamine are
series of bacterial strains.” to a specific site in the antibiotics, dubbed the
independent9. Going forward, studies that use C14 position6. The addition of an acetyl group
dissociative drugs in people will continue to be prohibitively slow and impractical at large produces a molecular bump that clashes with
of great interest — for instance, to reveal the scales. Li et al.5 report on page 145 how a mod- ribosome-bound RNA in the PTC, and thus
connection (if any) between the brain rhythm ular synthesis of the structurally complex anti- blocks antibiotic activity (Fig. 1).
reported by Vesuna et al. and the various desir- bacterial compound virginiamycin M2 (VM2), There have been several attempts to prepare
able properties of ketamine. Such studies based on easily interchangeable molecular derivatives of group A streptogramins that
should also include medicines, such as benzo­ building blocks, has provided access to VM2 could avoid this deactivation mechanism7. But,
diazepines and lamotrigine, that attenuate derivatives that could not previously have in each case, the derivatives were limited to
ketamine-induced dissociation. An improved been prepared — and has thereby enabled the those that could be prepared from the natural
understanding of how ketamine alters brain rational development of a variant that evades product itself, through a process called semi-
rhythms and associated behavioural states an ancient resistance mechanism. synthesis, and were found not to be resistant
could eventually lead to therapeutics for Virginiamycin M2 belongs to the strepto- to VatA-mediated deactivation. Researchers
people experiencing chronic pain, depression gramin family of antibiotics, which is sub­ from the same group as Li and colleagues pre-
and perhaps dissociative disorders. divided into groups A and B. The two groups viously developed8 a highly modular synthesis

32 | Nature | Vol 586 | 1 October 2020

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