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.

Star-Shaped Glial Cells Act as the Brain’s “Motherboard”

The transistors and wires that power our electronic devices need to be mounted on a base material known as a “motherboard.” Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.

But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University’s Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.

Using models designed to mimic brain signalling, De Pittà’s research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually “smart” in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain’s circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.

Transcending boundaries

"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."

Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.

De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.

Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.

These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.

A break in communication

According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain’s communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.

In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer’s disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.

Hypothalamic control of energy balance: insights into the role of synaptic plasticity

The past 20 years witnessed an enormous leap in understanding of the central regulation of whole-body energy metabolism. Genetic tools have enabled identification of the region-specific expression of peripheral metabolic hormone receptors and have identified neuronal circuits that mediate the action of these hormones on behavior and peripheral tissue functions. One of the surprising findings of recent years is the observation that brain circuits involved in metabolism regulation remain plastic through adulthood. In this review, we discuss these findings and focus on the role of neurons and glial cells in the dynamic process of plasticity, which is fundamental to the regulation of physiological and pathological metabolic events.

Chance finding reveals new control on blood vessels in developing brain

Zhen Huang freely admits he was not interested in blood vessels four years ago when he was studying brain development in a fetal mouse.

Instead, he wanted to see how changing a particular gene in brain cells called glia would affect the growth of neurons.

The result was hemorrhage, caused by deteriorating veins and arteries, and it begged for explanation.

"It was a surprising finding," says Huang, an assistant professor of neuroscience and neurology at the University of Wisconsin-Madison. "I was mainly interested in the neurological aspect, how the brain develops and wires itself to prepare for all the wonderful things it does."

But chance favors the prepared mind, as Louis Pasteur said, and Huang knew he needed to follow up on the suggestion that glia, normally considered “helpers” for the neurons, would affect the growth of blood vessels. For one thing, blood flow is a big deal in the brain, says Huang, whose collaborators included Shang Ma, in the graduate program in cellular and molecular biology at UW-Madison. “We know the brain is very energy-intensive. Per unit of volume, it consumes 10 times as much oxygen as the rest of the body.”

Although it makes intuitive sense that blood vessel development should be guided by neuronal development in some fashion, Huang spent years making sure he wasn’t being mislead by his experiment. Now, he’s satisfied himself, and his scientific reviewers, and the journal PLOS Biology has just published his study.

Aggressive Brain Tumors Can Originate From a Range of Nervous System Cells

Scientists have long believed that glioblastoma multiforme (GBM), the most aggressive type of primary brain tumor, begins in glial cells that make up supportive tissue in the brain or in neural stem cells. In a paper published October 18 in Science, however, researchers at the Salk Institute for Biological Studies have found that the tumors can originate from other types of differentiated cells in the nervous system, including cortical neurons.

GBM is one of the most devastating brain tumors that can affect humans. Despite progress in genetic analysis and classification, the prognosis of these tumors remains poor, with most patients dying within one to two years of diagnosis. The Salk researcher’s findings offer an explanation for the recurrence of GBM following treatment and suggest potential new targets to treat these deadly brain tumors.

"One of the reasons for the lack of clinical advances in GBMs has been the insufficient understanding of the underlying mechanisms by which these tumors originate and progress," says Inder Verma, a professor in Salk’s Laboratory of Genetics and the Irwin and Joan Jacobs Chair in Exemplary Life Science.

To better understand this process, Verma’s team harnessed the power of modified viruses, called lentiviruses, to disable powerful tumor suppressor genes that regulate the growth of cells and inhibit the development of tumors. With these tumor suppressors deactivated, cancerous cells are given free rein to grow out of control.

Cajal’s histological preparations and drawings showing some contributions to glial cells. (A) Fibrous astrocyte in the white matter of adult brain (formalin-uranium nitrate and gold-sublimated chloride); (B) Protoplasmic astrocyte in an adult brain (silver carbonate (del Rio) and formalin-uranium nitrate); (C) Twin astrocytes in the human hippocampus (formalin-uranium nitrate); (D) Fibrous astrocytes from the white substance of adult brain (Golgi methods); (E) Olygodendrocytes (ammoniacal silver oxide and Nissl); (F) Microglia cells (ammoniacal silver oxide, reduced silver nitrate and silver carbonate (del Rio) methods).

Source: The Histological Slides and Drawings of Cajal