“We really don’t understand what makes the human brain special,” said Ed Lein, Ph.D., Investigator at the Allen Institute for Brain Science. “Studying the differences at the level of cells and circuits is a good place to start, and now we have new tools to do just that.”

In a new study published today in the journal Nature Neuroscience, Lein and his colleagues reveal one possible answer to that difficult question. The research team, co-led by Lein and Gábor Tamás, Ph.D., a neuroscientist at the University of Szeged in Szeged, Hungary, has uncovered a new type of human brain cell that has never been seen in mice and other well-studied laboratory animals.

Tamás and University of Szeged doctoral student Eszter Boldog dubbed these new cells “rosehip neurons” — to them, the dense bundle each brain cell’s axon forms around the cell’s center looks just like a rose after it has shed its petals, he said. The newly discovered cells belong to a class of neurons known as inhibitory neurons, which put the brakes on the activity of other neurons in the brain.

The study hasn’t proven that this special brain cell is unique to humans. But the fact that the special neuron doesn’t exist in rodents is intriguing, adding these cells to a very short list of specialized neurons that may exist only in humans or only in primate brains.

The researchers don’t yet understand what these cells might be doing in the human brain, but their absence in the mouse points to how difficult it is to model human brain diseases in laboratory animals, Tamás said. One of his laboratory team’s immediate next steps is to look for rosehip neurons in postmortem brain samples from people with neuropsychiatric disorders to see if these specialized cells might be altered in human disease.

When different techniques converge

In their study, the researchers used tissue samples from postmortem brains of two men in their 50s who had died and donated their bodies to research. They took sections of the top layer of the cortex, the outermost region of the brain that is responsible for human consciousness and many other functions that we think of as unique to our species. It’s much larger, compared to our body size, than in other animals.

“It’s the most complex part of the brain, and generally accepted to be the most complex structure in nature,” Lein said.

Tamás’ research lab in Hungary studies the human brain using a classical approach to neuroscience, conducting detailed examinations of cells’ shapes and electrical properties. At the Allen Institute, Lein leads a team working to uncover the suite of genes that make human brain cells unique from each other and from the brain cells of mice.

Several years ago, Tamás visited the Allen Institute to present his latest research on specialized human brain cell types, and the two research groups quickly saw that they’d hit on the same cell using very different techniques.

“We realized that we were converging on the same cell type from absolutely different points of view,” Tamás said. So they decided to collaborate.

The Allen Institute group, in collaboration with researchers from the J. Craig Venter Institute, found that the rosehip cells turn on a unique set of genes, a genetic signature not seen in any of the mouse brain cell types they’ve studied. The University of Szeged researchers found that the rosehip neurons form synapses with another type of neuron in a different part of the human cortex, known as pyramidal neurons.

This is one of the first studies of the human cortex to combine these different techniques to study cell types, said Rebecca Hodge, Ph.D., Senior Scientist at the Allen Institute for Brain Science and an author on the study.

“Alone, these techniques are all powerful, but they give you an incomplete picture of what the cell might be doing,” Hodge said. “Together, they tell you complementary things about a cell that can potentially tell you how it functions in the brain.”

How do you study humanity?

What appears to be unique about rosehip neurons is that they only attach to one specific part of their cellular partner, indicating that they might be controlling information flow in a very specialized way.

If you think of all inhibitory neurons like brakes on a car, the rosehip neurons would let your car stop in very particular spots on your drive, Tamás said. They’d be like brakes that only work at the grocery store, for example, and not all cars (or animal brains) have them.

“This particular cell type — or car type — can stop at places other cell types cannot stop,” Tamás said. “The car or cell types participating in the traffic of a rodent brain cannot stop in these places.”

The researchers’ next step is to look for rosehip neurons in other parts of the brain, and to explore their potential role in brain disorders. Although scientists don’t yet know whether rosehip neurons are truly unique to humans, the fact that they don’t appear to exist in rodents is another strike against the laboratory mouse as a perfect model of human disease — especially for neurological diseases, the researchers said.

“Our brains are not just enlarged mouse brains,” said Trygve Bakken, M.D., Ph.D., Senior Scientist at the Allen Institute for Brain Science and an author on the study. “People have commented on this for many years, but this study gets at the issue from several angles.”

“Many of our organs can be reasonably modeled in an animal model,” Tamás said. “But what sets us apart from the rest of the animal kingdom is the capacity and the output of our brain. That makes us human. So it turns out humanity is very difficult to model in an animal system.”

“We always thought that immune cells from our arms and legs traveled via blood to damaged brain tissue. These findings suggest that immune cells may instead be taking a shortcut to rapidly arrive at areas of inflammation,” said Francesca Bosetti, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which provided funding for the study. “Inflammation plays a critical role in many brain disorders and it is possible that the newly described channels may be important in a number of conditions. The discovery of these channels opens up many new avenues of research.”

Using state-of-the-art tools and cell-specific dyes in mice, Matthias Nahrendorf, M.D., Ph.D., professor at Harvard Medical School and Massachusetts General Hospital in Boston, and his colleagues were able to distinguish whether immune cells traveling to brain tissue damaged by stroke or meningitis, came from bone marrow in the skull or the tibia, a large legbone. In this study, the researchers focused on neutrophils, a particular type of immune cell, which are among the first to arrive at an injury site.

Results in mouse brains showed that during stroke, the skull is more likely to supply neutrophils to the injured tissue than the tibia. In contrast, following a heart attack, the skull and tibia provided similar numbers of neutrophils to the heart, which is far from both of those areas.

Dr. Nahrendorf’s group also observed that six hours after stroke, there were fewer neutrophils in the skull bone marrow than in the tibia bone marrow, suggesting that the skull marrow released many more cells to the injury site. These findings indicate that bone marrow throughout the body does not uniformly contribute immune cells to help injured or infected tissue and suggests that the injured brain and skull bone marrow may “communicate” in some way that results in a direct response from adjacent leukocytes.

Dr. Nahrendorf’s team found that differences in bone marrow activity during inflammation may be determined by stromal cell-derived factor-1 (SDF-1), a molecule that keeps immune cells in the bone marrow. When levels of SDF-1 decrease, neutrophils are released from marrow. The researchers observed levels of SDF-1 decreasing six hours after stroke, but only in the skull marrow, and not in the tibia. The results suggest that the decrease in levels of SDF-1 may be a response to local tissue damage and alert and mobilize only the bone marrow that is closest to the site of inflammation.

Next, Dr. Nahrendorf and his colleagues wanted to see how the neutrophils were arriving at the injured tissue.

“We started examining the skull very carefully, looking at it from all angles, trying to figure out how neutrophils are getting to the brain,” said Dr. Nahrendorf. “Unexpectedly, we discovered tiny channels that connected the marrow directly with the outer lining of the brain.”

With the help of advanced imaging techniques, the researchers watched neutrophils moving through the channels. Blood normally flowed through the channels from the skull’s interior to the bone marrow, but after a stroke, neutrophils were seen moving in the opposite direction to get to damaged tissue.

Dr. Nahrendorf’s team detected the channels throughout the skull as well as in the tibia, which led them to search for similar features in the human skull. Detailed imaging of human skull samples obtained from surgery uncovered the presence of the channels. The channels in the human skull were five times larger in diameter compared to those found in mice. In human and mouse skulls, the channels were found in the both in the inner and outer layers of bone.

Future research will seek to identify the other types of cells that travel through the newly discovered tunnels and the role these structures play in health and disease.

This study was supported by NINDS (NS084863) and the NIH’s National Heart, Lung and Blood Institute (HL139598).

Quantum wells of the highest quality are typically fabricated by molecular beam epitaxy (sequential growth of crystalline layers), which is a well-established technique. However, it poses two major limitations: Lattice-matching is required, restricting the freedom in materials to choose from, and the thermal growth causes atomic diffusion and increases interface roughness.

2D materials can overcome these limitations since they naturally form a quantum well with atomically sharp interfaces. They provide defect free and atomically sharp interfaces, enabling the formation of ideal QWs, free of diffusive inhomogeneities. They do not require epitaxial growth on a matching substrate and can therefore be easily isolated and coupled to other electronic systems such as Si CMOS or optical systems such as cavities and waveguides.

Surprisingly enough, intersubband transitions in few-layer 2D materials had never been studied before, neither experimentally nor theoretically. Thus, in a recent study published in Nature Nanotechnology, ICFO researchers Peter Schmidt, Fabien Vialla, Mathieu Massicotte, Klaas-Jan Tielrooij, Gabriele Navickaite, led by ICREA Prof at ICFO Frank Koppens, in collaboration with the Institut Lumière Matière — CNRS, Technical University of Denmark, Max Planck Institute for the Structure and Dynamics of Matter, CIC nanoGUNE, and the National Graphene Institute, report on the first theoretical calculations and first experimental observation of inter-sub-band transitions in quantum wells of few-layer semiconducting 2D materials (TMDs).

In their experiment, the team of researchers applied scattering scanning near-field optical microscopy (s-SNOM) as an innovative approach for spectral absorption measurements with a spatial resolution below 20 nm. They exfoliated TMDs, which comprisedterraces of different layer thicknesses over lateral sizes of about a few micrometers. They directly observed the intersubband resonances for these different quantum well thicknesses within a single device. They also electrostatically tuned the charge carrier density and demonstrated intersubband absorption in both the valence and conduction band. These observations were complemented and supported with detailed theoretical calculations revealing many-body and non-local effects.

The results of this study pave the way towards an unexplored field in this new class of materials and offer a first glimpse of the physics and technology enabled by intersubband transitions in 2D materials, such as infrared detectors, sources, and lasers with the potential for compact integration with Si CMOS.

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