Pilot Grants Seek Answers to Critical Neuroscience Questions

Yvonne Ulrich-Lai, PhD, and James Herman, PhD. Photo by UC Academic Health Center Communications Services.

Obesity, spinal cord injury, and changes in the brain from severe adolescent stress or college football are the subjects of four $25,000 pilot grants awarded this year to researchers by the University of Cincinnati Gardner Neuroscience Institute, one of four institutes of the UC College of Medicine and UC Health, and the Network for Neuroscience Discovery. The pilot grants are intended to help the researchers gain preliminary data that can be used in applications for larger grants from the National Institutes of Health (NIH).

Winners of the grants, announced by UCNI Administrative Director Anya Sanchez, MD, MBA:

•   Jon Divine, MD, Associate Professor in the Department of Orthopedics, and Caleb Adler, MD, Associate Professor in the Department of Psychiatry and Behavioral Neuroscience, for a clinical trial, “Evidence of Neuropathic Changes in College Football Players.”
•    Richard Komoroski, PhD, Research Professor in the Department of Psychiatry and Behavioral Neuroscience, for his basic science project, “Disruption of Corticolimbic Connectivity by Stress.”
•    Yvonne Ulrich-Lai, PhD, Assistant Professor in the Department of Psychiatry and Behavioral Neuroscience, for her basic science project, “Stress, Obesity, and Endocrine FGF Actions in the Brain.”
•    Yutaka Yoshida, PhD, Assistant Professor of Pediatrics, and Mark Baccei, PhD, Assistant Professor in the Department of Anesthesiology, for their basic science project, “Properties of Interneurons Before and After Spinal Cord Injury.”

Dr. Divine, who is team physician for the University of Cincinnati Bearcats, and Dr. Adler will perform their study at the Center for Imaging Research at UC. The physicians seek to gather data on the potential impact on college football players of blows to the head, comparing the brain scans of UC football players, who play a high-impact contact sport, to the scans of UC athletes whose sport (such as swimming) involves more limited contact.

Cal Adler, MD

“Increasing attention is being paid to the potential effects of contact sports, particularly football, on the cognitive and psychological state of players,” Dr. Adler says. “Over one million high school students actively participate in football programs each year, as do over 60,000 college athletes. Newer data is now suggesting that the blows to the head often sustained during play may carry significant risks to these amateur participants.”

The researchers will scan the brains of UC football players who have suffered a concussion and are in their last year of competition. Three types of scans will be performed: magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) while the athlete is performing a working memory task.

The scans will enable the researchers to examine gray and white matter changes in the brain as well as functional activity in the prefrontal cortex, the area of the brain responsible for problem-solving, complex cognition and the moderation of social behavior. The researchers’ sobering hypothesis is that the brain scans of football players will show evidence of injury when compared to those of the athletes who play non-contact sports.

Dr. Komoroski

Dr. Komoroski and his team will study the potential for stress in adolescence in an animal model to permanently affect the brain. The adolescent period in humans coincides with the final-stage development of connectivity between the prefrontal cortex and the amygdala, a key brain circuit that is compromised in depressive illness. “Adversity during adolescence may impair the final development of this key emotional regulatory pathway, resulting in inappropriate mood regulation,” Dr. Komoroski says.

The team will use state-of-the-art neuroimaging methods to test whether exposing an adolescent animal model to chronic stress will produce short-term and long-lasting structural changes in brain circuitry, especially in females. The animal models will be scanned prior to stress exposure, after stress exposure and as adults.

“The study will determine whether stress affects the development of key emotional regulatory brain regions, which would lay the groundwork for use of structural endpoints as biomarkers or predictors of stress-related diseases in humans,” says co-investigator James Herman, PhD, Professor in the Department of Psychiatry and Behavioral Neuroscience.

Drs. Yoshida and Baccei

Normal movement requires precise interactions between a pathway from the brain called the corticospinal tract and the spinal cord circuits responsible for activating the appropriate muscles. These circuits include both motor neurons (which connect to muscles) and interneurons (cells that connect neurons to other neurons).  Following spinal cord injury (SCI), two problems prevent the nervous system from repairing itself and restoring motor function.

First, the corticospinal tract has been damaged. Second, injury-evoked changes in the spinal neurons contacted by this descending pathway could disrupt their ability to generate the correct output signals to muscles.

While much effort has been dedicated to enhancing the regeneration of the descending corticospinal fibers following damage to the spinal cord, the proposed studies by Drs. Yoshida and Baccei (pronounced Ba-SHAY) will be the first to identify alterations in the spinal interneurons that are directly connected to this corticospinal pathway. To date, the plasticity of interneurons has received far less study than the plasticity of motor neurons following SCI. The UC researchers hope to better understand the effects of spinal cord injury on the electrophysiological properties of these important cells, and they hope to determine the extent to which changes following spinal cord injury can be reversed.

Dr. Ulrich-Lai

Dr. Ulrich-Lai and her team will study two specific hormones that are important new potential therapeutic targets for obesity. The hormones are growth factors FGF19 and FGF21. Dr. Ulrich-Lai wants to identify regions of the brain in an animal model that should be targeted for interventions that can disrupt FGF-19/21 receptor signaling. In doing so, she aims to point the way toward the development of novel treatment targets for stress and metabolic diseases such as obesity and diabetes.

Both FGF19 and 21 are produced by the body naturally, but under different circumstances, and are related to eating or not eating, Dr. Ulrich-Lai says. “F19 is a response to a meal and F21 is a response to ketosis, which occurs after fasting or a low-carbohydrate diet. Our hypothesis is that they are signaling in the brain to effect obesity and stress processes. But because this is an exploratory work, so we do not actually know that this is the case.”

Dr. Ulrich-Lai hypothesizes that the hormones probably function in different brain regions but are signaling through the same receptor complex. “We do not really know what their role is,” Dr. Ulrich-Lai says. “However, these are hot new targets, recently discovered hormones in this family of atypical endocrine fibroblast growth factors. This family has been around for a while, and most of the hormones act locally in the tissue in which they are produced. But this subset of the family is unique because it can be a hormone: it can get into the blood and circulate and act on distant targets. Our research is novel because we are looking at the brain as a distant target.”

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