UND medical school researcher probes brain for anxiety clues The School of Medicine and Health Sciences neuroscientist Saobo Lei has been awarded a prestigious and highly competitive R01 five-year grant totaling $1.52 million by the National Institutes of Health (NIH) to study the cell-level mechanism that triggers anxiety. “Anxiety is among the most common psychiatric disorders and affects about 20 million American people,” says Lei, assistant professor in the medical school’s Department of Pharmacology, Physiology and Therapeutics. “Everyone at some time or another feels anxious, sometimes enough to warrant medical treatment. Anxiety is treatable with drugs, but only with moderate success because scientists still do not have a complete picture of the brain mechanisms that produce it. Moreover, most available anti-anxiety medications have side effects—sometimes very serious—or they create problems with tolerance or dependence, Lei says. “So it is of significant interest to further explore these anxiety-producing mechanisms in the brain,” says Lei, who grew up in central China and obtained his medical degree there. “Of course, we expect our research to lead to novel and much more effective therapeutic strategies to deal with anxiety.” Lei and his team of researchers at the UND medical school are testing the role of cholecystokinin, a neuropeptide, in anxiety. Peptides are relatively short chains of amino acids (ingredients in the molecular makeup of our DNA and proteins). Proteins are made up of very long peptide chains. Neuropeptides are protein-like molecules made in the brain. CCK was originally discovered in the gastrointestinal tract, but it is the most abundant neuropeptide in the brain, Lei notes. It’s long been known that CCK triggers anxiety, but no one knows exactly how it works. “We want to figure out how CCK increases anxiety,” says Lei, whose research center is part of the medical school’s free-standing Neuroscience Laboratory. “After we know the mechanisms by which CCK increases anxiety, we will explore whether drugs that reduce the function of CCK system in the brain can be used to treat anxiety.” That means Lei and his team must pry open the secret of how anxiety is produced. “There is some recently compelling evidence that anxiety is related to an increase in the function of glutamate system in the brain,” he says. Glutamate -- the same compound that’s in the widely used flavor-enhancing ingredient MSG -- is an excitatory neurotransmitter in the brain. Glutamate can be released from one neuron and activate glutamate receptors on another neuron to make the second neuron more excited. Increases in the excitability of neurons in the brain can produce anxiety, Lei explains. “Because CCK is a natural substance in the brain, we want to test whether and how CCK changes the functions of glutamate in the brain,” Lei says. “We want to test the hypothesis that CCK increases anxiety by enhancing glutamate release and up-regulating glutamate receptor functions. We will also test whether down-regulation of the functions of CCK system such as using CCK receptor inhibitors or knocking out the genes for CCK and CCK receptors reduces anxiety.” “Basically, we are trying to find out whether modulation of CCK system can serve as a novel way to treat anxiety,” Lei says. Lei’s five-year NIH RO1 grant will support several researchers and their lab activities related to the anxiety research project. The R01—or Research Project Grant—is the original and historically oldest grant mechanism used by NIH. The R01 supports health-related research and development based on the mission of the NIH. The NIH awards R01 grants to organizations of all types (universities, colleges, small businesses, for-profit, foreign and domestic, faith-based, etc.). The R01 mechanism allows an investigator to define the scientific focus or objective of the research based on a particular area of interest and competence. Although the Project Director/Principal Investigator writes the grant application and is responsible for conducting the research, the applicant is the research organization.