Neuron to Neuron: Cox Studies Behavior at the Cellular Level

NeuroTech group member Charles Cox studies how neurons communicate at the synaptic level in order to gain insight into the cellular mechanisms that underlie cognitive function and behavior.

Charles "Lee" Cox didn't focus on epilepsy as a research topic for personal reasons, even though that would have been understandable. There is a history of the disease in his family, but Cox's interest in epilepsy was spurred by what he thought it could tell science about how our brains work.

"What triggered it for me in my initial studies was that I was very interested in learning and memory at the cellular level," said Cox, who is best known on campus as Lee. "I was a psychology major and I was in a traditional physiological psychology graduate program. One of the big interests of ours that excited me was trying to understand at the cellular level what underlies learning and memory. Is there a "learning cell" and what are the particular mechanisms that give rise to it?"

"We're studying the basic language of the brain, how neurons communicate, and we're really interested in the long term communication between neurons.
- Charles "Lee" Cox

That research path Cox began during his grad school days continues today as a member of the NeuroTech group at the Beckman Institute. An Associate Professor in the Illinois Department of Molecular and Integrative Physiology and the Department of Pharmacology in the College of Medicine, Cox studies the cellular mechanisms underlying behavior and cognitive functions. He and his group investigate topics like sensory processing and neuronal excitability with a focus on the thalamus which, from its position on top of the brainstem, relays information from different parts of the brain to and from the cerebral cortex.

"We're basically asking the most fundamental questions about how neurons talk to each other and learning their language," Cox said. "That's really the nuts and bolts of it. If you build up from there, neurons give rise to behavior and a lot of different neurological conditions as well."

That is what led him to study epilepsy.

"Epilepsy is basically neurons that have gone a little crazy, hyperexcitability," Cox said. "We're studying the basic language of the brain, how neurons communicate and we're really interested in the long term communication of neurons. If you look at what we know about mechanisms of learning and memory at the cellular level it's basically a heightened amount of excitation that is long-lasting.

"If you go increase the excitability further, you can get to a state where there is hyperexcitability that can lead to runaway excitation resulting in epileptic discharge. So many mechanisms that scientists think are involved in epilepsy are the same mechanisms that are likely involved in cellular learning."

Lee was on an epilepsy training grant as a postdoctoral researcher but, again, his interest had to do with what the disease revealed about the mechanics of neuronal communication.

"My father has epilepsy," Cox said. "This has always been the interesting thing: I never really thought about studying epilepsy but I have kind of done it in a roundabout way. In the beginning I was just excited to study synaptic physiology."

Cox's specific interest in the area of synaptic physiology has to do with the role of longer-lasting signals between neurons and their action in brain function. He focuses on thalamocortical circuitry because of the important role that the thalamus plays in relaying information.

"You can almost think of the thalamus as a structure that is basically like, let's say, the core of a head of lettuce," he said. "And it connects to the whole outside sheet of a head of lettuce. So it's in a unique position to tie things together."

Cox said the thalamus ties things together by integrating and synchronizing the shorter and longer-lasting neuronal signals that power brain function.

"In regards to sensory processing, the thalamus is a region where a lot of information integration occurs before reaching the neocortex," Cox said. "There is increasing evidence suggesting the thalamus may play an important role in synchronizing cortical regions. You also can think of it as the freeway of sensory perception. Sensory information has to go through this before it goes out to the rest of the neocortex, or the outer covering of the brain."

Cox said behavioral activities are the result of a concerted effort by multiple neuronal systems; he focuses on those longer-lasting signals because of the crucial role they play in that effort.

"When you think about things such as arousal, and attention, one can think of those more as a lasting effect and that leads us to this idea of what are lasting signals," he said. "Our work is focused on understanding these mediators of long-lasting communication. Additionally, how do these long-lasting changes in communication then influence short-term communication? That's where you can get the binding of multiple neuronal circuits."

Cox explains the importance of this research line for understanding brain function on his Web site: "information integration at the single cell level is very critical, as well as the role of these individual cells in circuit based activities. Long-lasting modifications in neuronal excitability (i.e., neuromodulation, synaptic plasticity) have also been hypothesized to be the cellular correlates underlying these behavioral activities."

"The more we learn about complex behaviors, the more we realize that somehow you need to synchronize neural activities together," Cox said. "If you look at the work that's been done with fMRI they clearly show the synchronization of different cortical during specific tasks. We're kind of are at the level below that, the nuts and bolts, trying to figure out how you can do it."

Cox said most of the previous research on signals has focused on the shorter-lasting neurotransmitters, which can produce stable, repeatable effects.

"A lot of these longer-lasting modulators produce subtle effects so you don't see these giant robust changes as with classical neurotransmitters," Cox said. "But once there is concerted actions by multiple modulators, then some of those changes will pop out."

As part of his research, Cox studies neuromodulators like neuropeptides that also mediate communication between neurons. He is involved in a collaboration looking at the role of neuropeptides, which are chemical compounds of amino acids in our brain that can affect everything from mood to memory formation to the immune system.

"My colleague Jonathan Sweedler is finding many novel neuropeptides with brain tissues," Cox said. "When I came to Illinois, one of our major focuses was on how neuropeptides alter neural activity in mammals. Surprising to us, we found that certain neuropeptides can produce robust changes in neural excitability similar to classical neurotransmitters. Given the large, growing number of peptides, one speculates that they must do something because they are present. What do they really do? So with better pharmacological tools we can actually attempt to learn how these peptides influence neural activity."

Cox also has a collaboration with Biological Intelligence co-chair William Greenough, who focuses on cellular mechanisms underlying learning and memory while investigating topics like Fragile X Syndrome, the most common inherited cause of mental impairment and the most common known genetic cause of autism.

"Bill showed me an image one time and pointed out the malformations of the dendrites in fragile X mice," Cox said. "Coming from an epilepsy background, my first question to him was 'do these patients or animals have epileptic seizures?' and they did. Approximately 25 to 30 percent of them have epilepsy. So I proceeded to say 'Bill we do a lot of in vitro work, primarily brain slices, and I asked has anyone looked at alterations in neural activity?' At that time there were few investigators. So that spurred us on and we came at it from the side of looking at neuronal excitability."

The effort resulted in a project on the topic of long-term potentiation and a Feb. 2007 PNAS paper, Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice, by Cox and graduate student Brian Wilson that challenged conventional wisdom. Cox said their work showed that drug development in this area should proceed with caution.

"I'm always more cautious than anything else," he said. "I think the jury is out as to the development of compounds in this area."

Cox earned his Master's and Ph.D. at the University of California Riverside, and did postdoctoral work at Stanford and State University of New York at Stonybrook. He came to Illinois in 2000 and became a faculty member at the Beckman Institute three years ago. Cox said he was drawn to Illinois because of the neuroscience program.

"The strength of the Illinois neuroscience program is that it's a very diverse group of investigators," he said. "There are two ways of doing this: you either have very focused groups of multiple investigators working on a couple of problems or you develop a diverse group that spans the range of neuroscience. Illinois has a very strong reputation for a nice, diverse neuroscience group."

Cox said he fills a particular niche in the NeuroTech group at Beckman.

"If you look at the NeuroTech group that is up here you have systems-level neuroscientists people like Al Feng and Mark Nelson and Tom Anastasio, and then you have investigators at both ends, molecular and/or behavior like Bill Greenough and Justin Rhodes," he said. "At the time, they didn't really have anyone doing any synaptic research or at the cellular level, so apparently I was a natural fit."

Cox's lab at Beckman was recently enhanced with a new two-photon microscope for high-resolution imaging of tissue. He said it allows them to look at synaptic activity in ways that weren't possible before, including imaging dendrites, the branched projections extending from neurons that serve as contact points and conduits for the brain's electrical signals.

"A lot of the things I talk about focus on how a cell integrates vast amounts of information," Cox said. "How does a cell that has thousands of synaptic contacts integrate the information? With the two-photon microscope we can look at the activity at the level of the synapse, a place that we could never access with conventional electrodes.

"Now with this new technology we can actually do sub-cellular types of imaging. In much of our work with these modulators, we think that their primary sites of actions are out on the dendrites. With this newer technology, we are hoping now to systematically test our hypotheses about dendritic function, when previously we could only speculate. We can now actually focus at the level of a single synapse."

So with a new microscope, developing collaborations, and recently granted tenure, Cox is expanding his research horizons.

"The opportunity here is great," he said. "Now we can do the more risky, interesting types of experiments."