image: Dr. Joe Z. Tsien is a neuroscientist at the Medical College of Georgia at Georgia Health Sciences University. view more
Credit: Phil Jones, GHSU Photographer
AUGUSTA, Ga. – He's built a smarter mouse and taken a snapshot of a memory in his efforts to decode the brain.
"We are looking at the software code that runs the brain machine," said Dr. Joe Z. Tsien, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University. Answering questions like how a memory forms and what it takes to conjure it up will provide the kind of objective biomarkers needed to better diagnose and treat debilitating brain disorders, such as Alzheimer's and schizophrenia, he noted. "(Doing otherwise would be) like trying to diagnose and treat diabetes if you didn't know it had anything to do with insulin and blood glucose."
Tsien's more than two decades of memory science have earned him the 2012 International Behavioural and Neural Genetics Society's Distinguished Scientist Award. He is being honored during the society's14th Annual Meeting May 15-19 in Boulder, Colo.
The society lauded the Co-Director of GHSU's Brain & Behavior Discovery Institute as a prominent leader in elucidating the molecular and neural mechanisms of learning and memory. He was noted as a pioneer in the development of Cre/loxP techniques, key tools for developing disease-specific animal models widely used by scientists to study divergent medical problems.
Cre/loxP techniques make use of a virus' ability to insert itself into the DNA – Tsien likens it to DNA scissors – to selectively remove or manipulate existing genes or even add disease genes to particular cells or organs. "You really want to know when you manipulate a certain gene, how that affects cognition or behavior, for example," Tsien said. "Cre/loxP gives you a tool to selectively manipulate any gene in a given cell type or tissue at a given time."
He's used it to help dissect how memories form, what they look like and how to selectively erase or even enhance them. A focal point for his studies is NMDA receptors, essentially small pores on brain cell membranes that let ions in, increasing brain cell activity and communication.
Tsien garnered international acclaim in 1999 by using genetic techniques to make "Doogie," a smart mouse that over-expresses a subunit of the NMDA receptor called NR2B. Young brains have more NR2B, which enables faster learning by leaving communication channels between brain cells open longer. A decade later, he used the same approach to produce the smart rat, Hobbie-J.
In some of his latest work, published in 2011 in the journal Neuron, Tsien showed that NMDA receptors in the basal ganglia, a clustering of cells involved in procedural memories such as habits, are critical to habit formation. He used Cre/loxP to selectively remove the receptors from dopaminergic neurons in adult mice, noting that if the gene for NMDA receptors had been deleted from the entire body before birth, the mice would not have survived.
Now he has early images of what a memory looks like once it becomes a habit and evidence of how a habit might be selectively erased. Tsien has done similar work documenting how declarative memories are made, what they look like and how to selectively erase them. "If you forget a memory, what happens to that neural network?" he mused. "Are the patterns formed to make the memory just gone? How can we restore them?"
The "image" of a memory is the unique electrical pattern relevant brain cells make as a memory is recalled. "The way we measure memory, whether it's a habit or episodic memory, is based on recall," Tsien said, but more object measurement is needed.
"You are nodding your head indicating you are listening to me, but are you just being polite? Is your mind really elsewhere? We are looking for real-time brain markers, the activity pattern markers that represent a particular thought and action. We are very fascinated by these types of questions," the researcher said. New avenues include social behavior, such as how friendships develop.
Tsien is the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology.