Brain Injury Awareness Month: Understanding the Underlying Neurobiological Mechanisms
Each month, we highlight ongoing biophysical research related to a disease/condition for which advocates are trying to raise awareness. Often, in the push to find the next cure/treatment for a given condition, the public forgets that those cures and treatments are based on fundamental research conducted to understand how systems, both large and small, within our bodies work. That is the work that Biophysical Society members are conducting everyday in their labs.
Since March is Brain Injury Awareness Month, we asked BPS member Les Satin, University of Michigan, to share his research on brain injuries with us. More information about brain injuries and the activities associated with the awareness month is available from the Brain Injury Association of America. Given that 1.7 million Americans sustain a brain injury every year, it is clear that fundamental research in this area is needed to improve treatments and outcomes for those individuals.
What is the connection between your research and brain injuries?
Mild to moderate traumatic brain injuries are a major health problem but there are currently no effective therapies for them. As these injuries involve changes in neuronal function and synaptic communication between surviving neurons, better understanding the underlying mechanisms may result in new pharmacologic treatments to reverse the alterations caused by TBI and restore normal function. In our research, we directly injure cortical pyramidal neurons and glia in vitro by mechanically deforming the cells to mimic the forces encountered in brain following a traumatic brain inury (TBI), and then we assess their functional changes.
Why is your research important to those concerned about brain injuries?
As there are currently no effective pharmacological approaches to treat patients with TBI, our work may reveal new strategies to treat patients with TBI to alleviate deficits in cognition, memory, mood and motor function.
How did you get into this area of research?
I was originally trained in neurobiology and always was interested in neuronal function and synaptic transmission but my involvement in TBI research came about after meeting researchers and clinicians at my former institution, Virginia Commonwealth University, which has been a center for TBI research for decades. Many of my colleagues there urged me to get involved because we knew so little about how TBI alters neuronal electrophysiology, an area in which I have expertise. This seemed like a good area of study because we could make novel contributions to a very important, and poorly understood clinical problem. I remain convinced that the field continues to suffer from the dearth of basic research performed into the underlying neurobiological mechanisms.
How long have you been working on it?
My lab first started working on TBI in the mid 1990s when my first graduate student Steve Tavalin found that stretch injured neurons exhibited a delayed depolarization that resulted from an NMDA receptor dependent loss of electrogenic Na pump activity. From that time forward, our continual work has led to a string of publications mainly involving changes in both excitatory and inhibitory synaptic function.
Have you had any surprise findings thus far?
Yes! Almost all of our findings have been surprises! Mildly injured neurons show a variety of changes after injury, yet these all seem to be very specific: we found reduced fast desensitization of AMPA receptors, reduced Mg2+ block of NMDA receptors, increased GABA-A receptor currents, and depressed AMP Aergic mEPSCs following a transient insertion of Ca- permeable AMPARs. We think the latter reflect altered glutamate receptor trafficking.
What is particularly interesting about the work from the perspective of other researchers?
I think the field at-large has appreciated the highly detailed and highly specific nature of our findings, which in general are in accord with a lot of other work done using more intact systems and less specific approaches. We have been a bit unique in the field because of our focus on understanding the function of surviving neurons rather than quantifying the extent of cell death produced by TBI. But that makes the work more stimulating, in my opinion.
What is particularly interesting about the work from the perspective of the public?
I think the work we do is so basic and the model so elegant that it can take some time to explain why we think the research is relevant. But I find that once I get across the idea that the forces we are applying to neurons “in a dish” are similar to those encountered by the brain of a person in an auto accident or a kid in a football game, or a soldier in Afghanistan who encountered an IED while driving his or her Humvee, I think the simplicity of the model, the basic nature of the information we can extract, and the possibility for scaling up the system to allow high throughput drug screening people get the point and find the work interesting. Plus, using our system as a “test bed” for new compounds or to test new hypotheses for TBI we can go forward to test these things in more intact models like fluid percussion or weight drop which are applied to whole animals.