Steps to Better Human Brains

The main obstacle to a more abundant human future is the relatively poor quality of the average human brain. If only we could grow better human brains, and somehow make existing brains work better. Scripps Institute researchers may have discovered one piece of the puzzle, in the longer quest to the development of better human brains.

In mammals, the cortex is made up of six distinct anatomic layers holding different types of excitatory neurons. They are not the uniform layers of a cake, but rather, they are more like the layers wrapped around an onion. The smaller lower layers, on the inside, host neurons that connect to the brain stem and spinal cord to help regulate essential functions such as breathing and movement. The larger upper layers, closer to the outer surface of the brain, contain neurons that integrate information coming in from the senses and connect across the two halves of the brain.

The upper layers are a "relatively young invention," evolutionarily speaking, having been greatly expanded during primate evolution, said Mueller. They give humans in particular the unique abilities to think abstractly, plan for the future and problem-solve.

Previously, it was thought that all cortical neurons -- those making up both the lower and upper layers -- came from the same type of stem cell, called a radial glial cell, or RGC. A neuron's fate was thought to be determined by the timing of its birth date. The Scripps Research team, however, showed that there is a distinct stem cell progenitor that gives rise to upper layer neurons, regardless of birth date or place.

...Published in the August 10, 2012 issue of the journal Science, the new research reveals how neurons in the uppermost layers of the cerebral cortex form during embryonic brain development. _SD

They are saying that they think they have discovered a type of stem cell which gives birth to upper layer neurons, which seem to constitute one important difference between higher mammalian brains in primates, and lower mammalian brains, in neuroarchitecture.

More intriguing, they think the stem cell will migrate into the upper cortical layers regardless of when it is introduced. Would you like more upper layer neurons?

Cerebral Cortical Layering

Another fascinating bit of brain research comes from MIT, recently published in Nature:

There are hundreds of different types of neuron in the brain; most are excitatory, while a smaller fraction are inhibitory. All sensory processing and cognitive function arises from the delicate balance between these two influences. Imbalances in excitation and inhibition have been associated with schizophrenia and autism.

"There is growing evidence that alterations in excitation and inhibition are at the core of many subsets of neuropsychiatric disorders," says Sur, who is also the director of the Simons Center for the Social Brain at MIT. "It makes sense, because these are not disorders in the fundamental way in which the brain is built. They're subtle disorders in brain circuitry and they affect very specific brain systems, such as the social brain."

In the new Nature study, the researchers investigated the two major classes of inhibitory neurons. One, known as parvalbumin-expressing (PV) interneurons, targets neurons' cell bodies. The other, known as somatostatin-expressing (SOM) interneurons, targets dendrites -- small, branching projections of other neurons. Both PV and SOM cells inhibit a type of neuron known as pyramidal cells.

To study how these neurons exert their influence, the researchers had to develop a way to specifically activate PV or SOM neurons, then observe the reactions of the target pyramidal cells, all in the living brain.

First, the researchers genetically programmed either PV or SOM cells in mice to produce a light-sensitive protein called channelrhodopsin. When embedded in neurons' cell membranes, channelrhodopsin controls the flow of ions in and out of the neurons, altering their electrical activity. This allows the researchers to stimulate the neurons by shining light on them.

The team combined this with calcium imaging inside the target pyramidal cells. Calcium levels reflect a cell's electrical activity, allowing the researchers to determine how much activity was repressed by the inhibitory cells.

"Up until maybe three years ago, you could only just blindly record from whatever cell you ran into in the brain, but now we can actually target our recording and our manipulation to well-defined cell classes," Runyan says.

...The MIT team found that these inhibitory signals have two distinct effects: Inhibition by SOM neurons subtracts from the total amount of activity in the target cells, while inhibition by PV neurons divides the total amount of activity in the target cells.

"Now that we finally have the technology to take the circuit apart, we can see what each of the components do, and we found that there may be a profound logic to how these networks are naturally designed," Wilson says.

..."Conceptually, inhibition by subtraction and division is a very nice distinction," says Tony Zador, a professor of neuroscience at Cold Spring Harbor Laboratory who was not involved in the research. "It's a joy when something as theoretically appealing as division and subtraction actually maps onto the physiological substrate in such a fundamental way."

Increased inhibition by PV neurons also changes a trait known as the response gain -- a measurement of how much cells respond to changes in contrast. Inhibition by SOM neurons does not alter the response gain.

The researchers believe this type of circuit is likely repeated throughout the brain and is involved in other types of sensory perception, as well as higher cognitive functions. _SD

The Scripps paper in Science and the MIT paper in Nature are looking at different levels of brain architecture and activity, with some overlap.

To understand the brain we will have to piece together brain activity at multiple levels, from the molecular and genetic, up to electro-neurologic activity associated with specific behaviours. The two studies above fall somewhere in the middle of the range.

The challenge is to define how different levels of brain activity overlap and interlock, affecting each other from the bottom up and from the top down.

At that point, we may be in a position to modify particular cortical circuits, and alter the activity of particular areas of the brain.

Putting ourselves in a position to safely add stem cells to specific layers of cortex, or to modify the patterns of cortical inhibition in specific areas of the brain, might yield surprising dividends. Once we can do those things safely and well, we may be in a position to attempt much grander achievements.

We are already at the point where we can grow spontaneously oscillating 3D neuronal networks in the lab. As we better understand how the distinct architecture of different networks in various parts of the brain, and how they function within the whole, we will be in a better position to grow custom cortical columns and centres in the lab, to match different parts of the cortex -- sensory, motor, and associative.

In the meantime, expect a great deal of advancement in brain-machine interfacing, as we move into a parallel, cyborg future.

Al Fin cognitivists would prefer to replace damaged or malfunctioning white and gray matter with living replacement tissue -- wetware. But while we are learning how to do that, a wide array of hardware replacements, augments, interfaces, and workarounds are likely to find use in brain trauma rehab, routine neurology and neurosurgery, and in routine mental health therapies.