Commands from the matrix: Cellular environment controls formation and activity of neuronal connections

Environment moulds behaviour - and not just that of people in society, but also at the microscopic level. This is because, for their function, neurons are dependent on the cell environment, the so-termed extracellular matrix. Researchers at the Ruhr-Universität have found evidence that this complex network of molecules controls the formation and activity of the neuronal connections. The team led by Dr. Maren Geißler und Prof. Andreas Faissner from the Department of Cell Morphology and Molecular Neurobiology reports in the “Journal of Neuroscience” in collaboration with the team of Dr. Ainhara Aguado, Prof. Christian Wetzel and Prof. Hanns Hatt from the Department of Cell Physiology.

Neurons and astrocytes in culture

In cooperation with Prof. Uwe Rauch from Lund University in Sweden, Bochum’s biologists examined cells from the brains of two mouse species: a species with a normal extracellular matrix and a species which lacked four components of the extracellular matrix due to genetic manipulation, namely the molecules tenascin-C, tenascin-R, neurocan and brevican. They took the cells from the hippocampus, a brain structure that is crucial for the long-term memory. The team not only examined neurons but also astrocytes, which are in close contact with the neurons, support their function and secrete molecules for the extracellular matrix.

Formation, stability and activity of the neuronal connections depend on the matrix

The researchers cultivated the neurons and astrocytes together for four weeks with a specially developed culture strategy. Among other things, they observed how many connections, known as synapses, the neurons formed with each other and how stable these were over time. If either the astrocytes or the neurons in the culture dish derived from animals with a reduced extracellular matrix, these synapses proved to be less stable in the medium term, and their number was significantly reduced. Together with the Department of Cell Physiology at the RUB and the University of Regensburg, the team also showed that the neurons with a mutated matrix showed lower spontaneous activity than normal cells. The extracellular matrix thus regulates the formation, stability and activity of the neuronal connections. The researchers also examined a special structure of the extracellular matrix, the so-called perineuronal nets, which the Nobel laureate Camillo Golgi first described more than a century ago. They were significantly reduced in the environment of genetically modified cells.

To Make Mice Smarter, Add A Few Human Brain Cells

For more than a century, neurons have been the superstars of the brain. Their less glamorous partners, glial cells, can’t send electric signals, and so they’ve been mostly ignored.

Now scientists have injected some human glial cells into the brains of newborn mice. When the mice grew up, they were faster learners. The study, published Thursday in Cell Stem Cell, not only introduces a new tool to study the mechanisms of the human brain, it supports the hypothesis that glial cells — and not just neurons — play an important role in learning.

The scientific obsession with neurons really began at the end of the 19th century. Spanish anatomy professor Santiago Ramon y Cajal used a special dye to stain brain tissue. Under the microscope, neurons were revealed in exquisite detail. “A dense forest,” Ramón y Cajal called it — a field of little branching cells that would soon be named neurons.

With beautiful ink drawings, Ramón y Cajal painstakingly mapped neural networks and slowly developed the theory that neurons are the telegraph lines of thought (an idea later embraced by Schoolhouse Rock). Every idea and memory — every aspect of learning — could be traced back to the electric signals sent between neurons. Ramón y Cajal won the Nobel Prize for his work, and scientists focused on neurons for the next century.

But neurons aren’t the only cells in the brain.

"We’ve overlooked half the brain," says Douglas Fields, a neuroscientist at the National Institutes of Health. "We’ve only been studying one kind of cell in the brain." The other kind of cell — glial cells — are at least as abundant as neurons. But early scientists thought they were so boring they didn’t even merit a singular noun. "Glia is plural — there is no singular," Fields says. "We have ‘neuron’ but we don’t have ‘glion.’ "

Glial cells lacked the ability to send electric signals, and most scientists thought they were housekeeping cells, helping provide nutrients and insulation.

It was only in the last decade or so that scientists realized glial cells were more than that. Special types of glial cells, called astrocytes, which are named for the star-like patterns of their cellular structure, have their own form of chemical signaling. They have the potential to coordinate whole groups of neurons. “Glia are in a position to regulate the flow of information through the brain,” Fields says. “This is all missing from our models.”

And there’s something else. This type of glial cell, these astrocytes, have changed a lot as humans have evolved, while neurons have pretty much stayed the same. A mouse neuron and a human neuron look so much alike, even experienced neuroscientists can’t tell them apart.

"I can’t tell the differences between a neuron from a bird or a mouse or a primate or a human," says Steve Goldman, a neuroscientist at the University of Rochester who has studied brain cells for decades. But Goldman says glial cells are easy to tell apart.

"Human glial cells — human astrocytes — are much larger than those of lower species," he says. "They have more fibers and they send those fibers out over greater distances."

The thought is maybe these glial cells have played a role in making humans smarter. So Goldman teamed up with this wife, Maiken Nedergaard, to test this idea.

They injected some human glial cells into the brains of newborn mice. The mice grew up, and so did the human glial cells. The cells spread through the mouse brain, integrating perfectly with mouse neurons and, in some areas, outnumbering their mouse counterparts. All the while Goldman says the glial cells maintained their human characteristics.

"They very much thought that they were in the human brain, in terms of how they developed and integrated," he says.

So what are these mice like, the ones with brains full of functioning human cells? Their neural circuitry is still just the same, so they act completely normal. They still socialize with other mice and still seem interested in mousey things.

But the researchers say these mice are measurably smarter. In classic maze tests, they learn faster. “They make many fewer errors, and it takes them less time to come to the appropriate answer,” Goldman says.

It might take a normal mouse four or five attempts to learn the correct route, for example. But a mouse with human brain cells could get it on the second try. Glial cells — those boring glial cells — somehow enhance learning.

In fact, they could be changing what it means to be a mouse, and that raises ethical questions for this kind of research.

"Maybe bioethicists have been a little bit too cavalier assuming that a mouse with some human brain cells in it is just your normal old mouse," says Robert Streiffer, a bioethicist from the University of Wisconsin-Madison. "Well, it’s not going to be human, but that doesn’t mean it’s a normal old mouse either."

Streiffer says it’s not just that these mice can get through a maze more quickly — they’re better at recognizing things that scare them. And perception of fear is one of the things bioethicists must weigh when they decide the types of experiments you can do on an animal.

"So you have to sort of step back and do some hardcore philosophy," he says. Like, will these types of human-animal hybrids eventually get close enough to humanity that we would feel uncomfortable performing experiments on them?

The researchers in this study say we’re really, really far from that point. And if you want to investigate the role of glial cells, these hybrid mice are the best tools available.

Fear really resides in a different area of the brain than its inhibitory mechanisms

Do you suffer from a phobia? Maybe arachnophobia? Then you know very well that even if you do not feel uneasy when imagining a huge and hairy tarantula in the therapist’s office, you still jump out of the shower screaming upon seeing a tiny spider. Why is it so hard to get rid of a phobia?

Extinguishing the fear response does not consist of erasing the memory of the fear provoking stimuli, but creating new, competitive memory traces. It has been suspected for some time that neuronal brain circuits responsible for extinguishing fear differ from circuits involved in reoccurrence of the fear response. This assumption has finally been experimentally confirmed. Novel experiments, described in PNAS, a prestigious journal of the American National Academy of Sciences, have been conducted by scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences and the International Institute of Molecular and Cell Biology in Warsaw. This research team was headed by Dr Ewelina Knapska, Dr Jacek Jaworski and Prof. Leszek Kaczmarek.

“Research has been carried out using a special, genetically modified strain of rats developed in the Nencki Institute. As a result we were able to observe the connections between neurons activated in the brains of animals experiencing fear”, explains Dr Ewelina Knapska, head of the Laboratory of Emotions Neurobiology in the Nencki Institute.