Francis Crick was hallucinating about the claustrum.

The 88-year-old biologist, best known for his role in discovering the DNA’s double helix structure, was dying of colon cancer. But a manuscript was weighing on his mind.

His friend and colleague Christof Koch, Ph.D., with whom he was writing the manuscript, had talked to him just a few days prior.

“He was a consummate scientist to the bitter end,” said Koch, Chief Scientist of the MindScope Program at the Allen Institute. “He said, ‘I have to go into the hospital, but don’t worry, I’ll take care of revisions to the paper.’”

Although Crick started his career studying the shape of DNA, he later turned to neuroscience, pursuing a special interest in consciousness. The manuscript the two were working on outlined an intriguing theory about whether the claustrum, a tiny and enigmatic brain structure present in all mammals, might be responsible for consciousness. Crick finished the promised revisions on the manuscript in those few days before his death, in July 2004, and his widow later told Koch that the day he died, the biologist had a high fever and thought he was having a conversation with Koch about claustrum neurons.

That paper, published in 2005, sparked a flurry of interest among neuroscientists in this little bit of the brain. Is the claustrum the seat of human consciousness? Spoiler: We still don’t know.

But recent studies from Koch and other scientists at the Allen Institute are revealing new insights about how the claustrum connects to the rest of the brain; the kinds of neurons that make it up (one of which is studded with receptors for common psychedelic drugs); and how it influences activity in the cortex, the wrinkled, outermost shell of the brain.

Border dispute

Part of the reason the claustrum poses so many mysteries is because it is so small and so hidden, making it tough to study in laboratory animals and difficult to visualize in humans. In the human brain, the claustrum is a thin, surfboard-shaped sheet of neurons underneath the cortex, one on either side of your brain, roughly under your temples. In the mouse, it’s more like two tiny boomerangs. In some species, the laboratory mouse included, it’s very difficult to define its edges, leading to even more confusion about what it does and who it talks to.

The claustrum is the most densely connected part of the brain by size — each cubic millimeter of this little sheet sends and receives more connections to and from other parts of the brain than any other region. All these connections led scientists to believe it must be doing something important, something big and overarching that would require the claustrum to be so tuned into the rest of the brain — something like consciousness, or maybe focusing attention, or making decisions.

One of the recent Allen Institute studies, led by Principal Scientist Quanxin Wang, Ph.D., Senior Scientist Yun Wang, Ph.D., Hongkui Zeng, Ph.D., Executive Vice President and Director of the Allen Institute for Brain Science, and Koch, delved into the traffic patterns of the mouse claustrum in more detail. That study, published earlier this month in the journal Cell Reports, used multiple methods to define the borders of the mouse claustrum.

Previously, scientists had five distinct definitions of the mouse claustrum, where it starts and where it ends. It’s like a border dispute on a micro-scale. How can you study what the claustrum does if you can’t even agree on what the claustrum is?

Quanxin Wang has dedicated much of his career to neuroanatomy, carefully tracing and analyzing each structure in the mouse brain to help create a consensus map for the community. Knowing the details of the claustrum’s boundaries was key to mapping the connections it makes, he said. Imagine you are trying to trace all the ingoing and outgoing phone calls from the state of Oregon — you couldn’t do that if you didn’t know where Oregon stops and Washington begins, down to the level of individual people in one state or the other. The team’s new study defines the borders of the claustrum at the level of cells, so scientists will now know exactly which neurons reside on either side.

“This is the beauty of neuroanatomy,” Quanxin Wang said. “It played a very important role in cracking the circuitry of the claustrum, making the data as regional and cell type-specific as possible. This can lead to further explorations of the claustrum’s function.”

High-wired

Quanxin Wang and his colleagues used two different types of neuron tracing — one that captures inputs, the other outputs — to study how the claustrum wires up with the rest of the brain. Consistent with previous research, they found that many different parts of the brain send signals to the claustrum, including nearly every part of the cortex. The prefrontal cortex, which is the part of your brain right under your forehead and is responsible for sophisticated cognitive functions like decision making, is especially well-connected to the claustrum. The claustrum sends connections to nearly all parts of the cortex in turn, but it barely sends outputs to other parts of the brain besides the cortex.

The team also looked at the different kinds of brain cells present in the claustrum, tracing their 3D shapes to better understand their diversity. They found nine distinct kinds of neurons based on their projection targets and trajectories, including some breathtakingly wide-ranging cells that send projections in a ring all the way around the mouse’s skull. Koch calls these cells “crown of thorns” neurons.

“They are up to 10 centimeters long inside a brain that fits comfortably within a sugar cube,” Koch said. (For reference, a sugar cube is a bit larger than a cubic centimeter.)

If that size relationship scales up in humans, our claustrum neurons could easily be around a meter or longer each, Koch said. The neurons that make up our sciatic nerve, which runs from the brain to the base of the spine, are about that long — but nobody’s yet seen such a massive neuron bundled entirely within the human brain.

Finally, the team found that the claustrum is chock full of serotonin 2A receptors, which is the main target of psychedelic drugs. Ongoing research at the Allen Institute has shown that mouse claustrum neurons and human cortical neurons that carry these receptors can respond to psylocibin, the active ingredient in magic mushrooms, and a study of humans taking psylocibin found that the drug alters how the claustrum signals to the cortex.

Complex control

All that was a brief and incomplete tour through the claustrum’s hardware, but as for its software — its activity and its influence on the rest of the brain’s activity — things get a bit squishier. Some studies in mice suggest that the claustrum is the big chiller of the brain, acting to switch off cortical activity, as in deep sleep. Keeping neural activity under tight control is important, as too much activity can lead to seizures.

But a recent study from another team at the Allen Institute suggests the claustrum’s influence on the cortex might be more complicated than just dampening activity. Led by Allen Institute Scientist Ethan McBride, Ph.D., and Investigator Shawn Olsen, Ph.D., the team surveyed more than 15,000 neurons in several different parts of the mouse cortex using Neuropixels, thin silicon probes that can capture the activity of hundreds of neurons in a single experiment. The researchers used a mouse genetically engineered to “switch on” neurons in the claustrum with a beam of light, and asked what happens to these 15,000 neurons when the claustrum is suddenly activated.

With very short pulses (a few milliseconds) of light to activate the claustrum, the scientists observed the general inhibition of the cortex seen in previous studies. But after a full half-second, they saw a mix of increased and decreased neural activity. How neurons changed their electrical activity depended in part on their location in the cortex. Getting that fuller picture required recording from many more neurons and using different timescales of claustrum activation.

“Previously, we thought there was just this blanket of inhibition,” Olsen said. “This is a much richer view of the ways the claustrum changes and controls the activity of the cortex.”

Still a mystery

Scientists who want to understand the function of a particular brain region in humans tend to look for subjects who happen to have an injury in that region, from a stroke or a head injury or virus-induced brain swelling. Because the claustrum is so thin and elongated, there aren’t many examples of people who have injury just to that region and no other. There are no known cases of a living person whose entire claustrum, and only the claustrum, was damaged or missing.

A recent review article from scientists at the University of Oxford tabulated the known claustrum injuries that had been described by other scientists and concluded that “the most consistent feature of these claustrum lesion studies is their inconsistency.” People with claustrum lesions suffer a grab bag of neurological and psychological symptoms: They often have seizures, some have trouble sleeping, some have paranoid delusions or other hallucinations — and two patients had what is known as “Cotard delusions,” a class of delusion where patients believe they are dead or otherwise don’t exist.

As in many other areas of science, the more data researchers gather about the claustrum, the murkier the picture gets. In Koch and Crick’s paper of nearly 20 years ago, the scientists proposed that the claustrum acts as a “conductor of the cortical symphony,” uniting activity from disparate brain regions in such a way that we end up with cohesive thoughts and perceptions. When you’re talking to a friend, different parts of your cortex process the sounds coming out of their mouth and the changing expressions on their face, but you perceive that conversation as a single thing rather than disjointed visual and auditory cues. Maybe the claustrum helps with that linking.

Relatedly, Koch thinks the region could play a role in narrowing attention. As you’re reading this article, maybe there are trees or cars or piles of work in your peripheral vision, and noises cascade behind you from your co-workers or family members or strangers on the bus. But you’re choosing to focus on just one of the many inputs that’s bombarding your senses right now. The claustrum could suppress what you’ve decided is less important in the moment.

“That’s my current best guess,” Koch said. For now, it’s still just a guess.

The Allen Institute studies described in this article were partially supported by the Tiny Blue Dot Foundation and by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under award number U19MH114830. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH and its subsidiary institutes.