Andrew Koob received his Ph.D. in neuroscience from Purdue University in 2005, and has held research positions at Dartmouth College, the University of California, San Diego, and the University of Munich, Germany. He's also the author of The Root of Thought, which explores the purpose and function of glial cells, the most abundant cell type in the brain. Mind Matters editor Jonah Lehrer chats with Koob about why glia have been overlooked for centuries, and how new experiments with glial cells shed light on some of the most mysterious aspects of the mind.



LEHRER: Your new book, The Root of Thought, is all about the power of glial cells, which actually make up nearly 90 percent of cells in the brain. What do glial cells do? And why do we have so many inside our head?



KOOB: Originally, scientists didn't think they did anything. Until the last 20 years, brain scientists believed neurons communicated to each other, represented our thoughts, and that glia were kind of like stucco and mortar holding the house together. They were considered simple insulators for neuron communication. There are a few types of glial cells, but recently scientists have begun to focus on a particular type of glial cell called the 'astrocyte,' as they are abundant in the cortex. Interestingly, as you go up the evolutionary ladder, astrocytes in the cortex increase in size and number, with humans having the most astrocytes and also the biggest. Scientists have also discovered that astrocytes communicate to themselves in the cortex and are also capable of sending information to neurons. Finally, astrocytes are also the adult stem cell in the brain and control blood flow to regions of brain activity. Because of all these important properties, and since the cortex is believed responsible for higher thought, scientists have started to realize that astrocytes must contribute to thought.



LEHRER: Why have glia been neglected for so long?



KOOB: To understand this, you have to take a tour of the history of brain science. Glia were mainly a sidebar for 200 years in the struggle over the idea of the neuron. A few highlights were: In the late 18th century, scientists discovered the electrical properties of the neuron in the spine of frogs. Neurons have long tethers that are easy to study called 'axons' that extend from the cell body from the brain into the spine and the spine out to the limbs and body. Similarly, neurons in the senses were linked to the neurons in the brain. This is where the notion of neurons as the base of our thoughts took root. In the mid-19th century, glia were just being discovered, and researchers figured the glial cells simply held the neurons together (glia is greek for glue). What I find sort of hilarious is that scientists stumbled upon a very numerous cell in the brain, an organ responsible for our thoughts and personality, but they were so focused on neurons that they concluded the new cell was worthless. In the late 19th century a staining method was developed to look at cells more effectively in the brain. A brilliant researcher from Spain, Santiago Ramon y Cajal, took it upon himself to study the brain from the perspective of neurons. He meticulously mapped out a scheme for how they process information and are connected, which led to "The Neuron Doctrine." ("The Neuron Doctrine" is a belief that neurons are responsible for our thoughts.) However, Cajal seemed inconvenienced by glial cells. They were very numerous and obviously hanging out all over the cortex. Meanwhile, his brother Pedro, who was also a scientist, developed the theory that glial cells were 'support cells' that insulated neuron electrical properties. Cajal decided to back his brother's theory. And since 1906 when he won the nobel prize, this has been the dogma.



LEHRER: Could you describe some of the early experiments that first led scientists to reconsider the role of glial cells?



KOOB: Glial experiments didn't get going until the 1960s. All scientists knew about glia was that if you put neurons in petri dish, you had to have glia, or neurons would die. Then, Stephen W. Kuffler at Harvard, for reasons unknown, decided to test Pedro's accepted theory of insulation. This was around same time that cell counts in the brain revealed glial cells to be nearly 90% of the brain (this is where the neuron based idea that we only use 10% of our brain comes from). Kuffler is notable because he ironically established the Harvard 'neuro' biology department while he was performing these groundbreaking glial experiments. Anyway, Kuffler took astrocytes from the leech and mud puppy and added potassium, something that is known to flow out of neurons after they are stimulated. He thought this would confirm Pedro's theory that glial cells were insulators. What he found instead was that the electrical potential of glial cells responded to potassium. Kuffler and colleagues found that astrocytes exhibited an electrical potential, much like neurons. They also discovered in the frog and the leech that astrocytes were influenced by neuronal ion exchange, a process long held to be the chemical counterpart to thought. Since then many researchers have completed experiments on the communicatory ability of glial cells with neurons, including in the late 80s and early 90s when it was discovered glial cells respond to and release 'neuro' transmitters.



LEHRER: Why are calcium waves important?



KOOB: In short, calcium waves are how astrocytes communicate to themselves. Astrocytes have hundreds of 'endfeet' spreading out from their body. They look like mini octopi, and they link these endfeet with blood vessels, other astrocytes and neuronal synapses. Calcium is released from internal stores in astrocytes as they are stimulated, then calcium travels through their endfeet to other astrocytes. The term 'calcium waves' describes the calcium release and exchange between astrocytes and between astrocytes and neurons. Scientists at Yale, most notably Ann H. Cornell-Bell and Steven Finkbeiner, have shown that calcium waves can spread from the point of stimulation of one astrocyte to all other astrocytes in an area hundreds of times the size of the original astrocyte. Furthermore, calcium waves can also cause neurons to fire. And calcium waves in the cortex are leading scientists to infer that this style of communication may be conducive to the processing of certain thoughts. If that isn't convincing, it was recently shown that a molecule that stimulates the same receptors as THC can ignite astrocyte calcium release.



LEHRER: You suggest that glia and their calcium waves might play a role in creativity. Could you explain?



KOOB: This idea stems from dreams, sensory deprivation and day dreaming. Without input from our senses through neurons, how is it that we have such vivid thoughts? How is it that when we are deep in thought we seemingly shut off everything in the environment around us? In this theory, neurons are tied to our muscular action and external senses. We know astrocytes monitor neurons for this information. Similarly, they can induce neurons to fire. Therefore, astrocytes modulate neuron behavior. This could mean that calcium waves in astrocytes are our thinking mind. Neuronal activity without astrocyte processing is a simple reflex; anything more complicated might require astrocyte processing. The fact that humans have the most abundant and largest astrocytes of any animal and we are capable of creativity and imagination also lends credence to this speculation.

Calcium is also released randomly and without stimulation from astrocytes' internal stores in small bursts called 'puffs.' These random puffs can lead to waves. It is possible that the seemingly random thoughts during dreams and sensory deprivation experience could be calcium puffs becoming waves in our astrocytes. Basically, it is obvious that astrocytes are involved in brain processing in the cortex, but the main questions are, do our thoughts and imagination stem from astrocytes working together with neurons, or are our thoughts and imagination solely the domain of astrocytes? Maybe the role of neurons is to support astrocytes.