UF researchers restore spatial deficits caused by stroke in rats

Building on years of basic science that helped pinpoint a region of the rat brain that affects spatial awareness, University of Florida researchers are now testing the ability of antibodies to restore brain function after a simulated stroke.

Scientists studying rats with spatial neglect syndrome — a cognitive disorder associated primarily with stroke in people — found that injections of molecules known as monoclonal antibodies into damaged regions of the animals’ brains encouraged existing neurons to sprout new growth, and restored normal spatial perception as assessed by observing behavior over a period of weeks. The National Institute of Mental Health recently awarded Roger Reep, Ph.D., and James Corwin, Ph.D., of Northern Illinois University, a three-year grant renewal totaling $989,000 for their ongoing research.

“What we’ve found is that the regions of the brain in which neglect syndrome occurs in humans have corresponding regions with similar function in rats,” said Reep, Ph.D., a professor of physiological sciences with UF’s College of Veterinary Medicine and a member of UF’s McKnight Brain Institute. “This means we can investigate mechanisms of neural repair, and so there’s hope for developing a therapy to promote recovery in humans. That’s the key insight.”

UF scientists used monoclonal antibodies, which interfere with the tendency of a naturally occurring protein to block neuron growth, in the laboratory. Researchers elsewhere already had shown the approach could restore movement in rats with spinal cord injuries. Never before, however, has the antibody, known as IN-1, been studied in relation to spatial neglect syndrome.

“In binding to the protein, the antibody keeps the protein’s growth-inhibiting characteristics from working as they would naturally in that particular region of the brain following brain injury,” said Joe Cheatwood, a graduate student in Reep’s laboratory.

“Our work is not directly clinical, but is designed to be hopefully translational, in that someone designing a clinical trial in people would be able to know what to expect for cognitive problems such as those seen in our neglect model,” he added.

It has long been known that people who have suffered a stroke typically lose not just physical function but also spatial awareness — how the world looks and one’s relationship to it — because regions on one side of the brain are suddenly dysfunctional, Reep said. These patients have a condition known as hemispatial neglect, a neurological disorder almost always associated with damage to the right side of the brain. Researchers say roughly half of those with a right hemisphere injury, about 25 percent of all victims of major stroke, experience the phenomenon known as neglect syndrome.

Every 45 seconds, someone in America has a stroke. About 700,000 Americans will have a stroke this year and more than 167,000 of them will die. Stroke is America’s No. 3 killer and one of the leading causes of disability, according to the American Stroke Association. Reep and his colleagues believe that an area of the brain known as the dorsocentral striatum receives and processes information important to attention and spatial perception. For more than 20 years, Reep and Corwin, an associate professor of psychology at Northern Illinois University, have studied the circuitry of the rat brain that corresponds to the human brain’s make-up. Of particular interest are the neurological connections from the cerebral cortex to the dorsocentral striatum, a previously unknown network of relationships that are ultimately linked to the brain’s ability to perceive space and direct attention, and that has proven crucial for recovery from neglect.

During this period, Reep has worked extensively with a rodent model developed with Corwin and fellow McKnight Brain Institute neurologists Kenneth Heilman, M.D., Robert Watson, M.D., and Edward Valenstein, M.D.

“We realized over time that the striatum was the location of changes that lead to temporary recovery that can be induced by pharmacological agents,” said Reep, whose studies on brain circuitry span a 20-year period, with funding provided primarily through the National Institutes of Health.

Reep said it is rewarding to see the longtime efforts of basic science pay off.

“What people generally think is that when you have a stroke, you get irrevocable damage, but our question has always been, what kinds of compensatory changes is the rest of the brain capable of making?” Reep said. “If you create the right environment, using, say, stem cells and antibodies, what parts of the brain are capable of repair?”

Spontaneous recovery from hemispatial neglect does not occur in rats, and is seldom seen in humans, Reep said, adding that when the human brain is damaged through a stroke, physiological changes occur in surrounding tissue. Reep’s team has simulated this effect in rats and diagrammed its findings with sophisticated imaging techniques that use digital superimposition and color coding to visualize the ways in which various neuron connections intermingle. That aspect of the researchers’ work was highlighted last year in the journal Brain Research. Reep also presented his findings at the most recent annual meeting of the Society for Neuroscience.

“The next step for this work is to combine a stroke model with the use of antibodies and stem cells, in an attempt to create the most favorable conditions for restoration of lost neural connections and behavioral recovery of function,” Reep said.