The study, done in rats, found that mini-strokes – a fairly common occurrence in an older brain – prevent a key brain chemical from carrying messages from nerve cell to nerve cell. The integrity of nerve cells that use this neurotransmitter, acetylcholine, depends on a steady blood flow.
A decrease in the number of nerve cell fibers, or axons, that use acetylcholine in the brain's cortex led to a decrease in the rats' mental function, said Martin Sarter, the study's lead author and a professor of both neuroscience and psychology at Ohio State.
The researchers injected into rats tiny microspheres – small beads that block blood flow – into the main artery that feeds brain tissue. The researchers wanted to mimic what happens in the brain during a small stroke. These small beads ultimately lodged in the tapering ends of blood vessels, where they stopped blood flow.
It's the first time that researchers have used this sort of model to look at the effects of cerebral blood flow disruption on mental functions that require intact nerve cells releasing acetylcholine in the cortex.
In patients with dementia, blood flow in the brain may slow down as a result of mini-strokes and the abnormal regulation of blood vessels, which contributes to the loss of normal mental function and, eventually, dementia.
The damage to the acetylcholine system as a result of reduced blood flow is harmful in several ways. For example, the cells that produce acetylcholine also seem to regulate blood vessel dilation and constriction in the brain.
"It becomes a vicious cycle," Sarter said. "The acetylcholine system controls blood flow in the cortex, or outer portion of the brain. But decreased blood flow harms the acetylcholine system, and as a result, the blood vessels aren't regulated normally."
As the acetylcholine system declines, so does the brain's ability to process information.
The researchers presented their findings on November 10 in New Orleans at the annual Society for Neuroscience meeting. Sarter conducted the study with John Mahoney, Tara Craft and Courtney DeVries, all with Ohio State's psychology department, and John Bruno, a professor of psychology and neuroscience at Ohio State.
The researchers injected the microspheres into the carotid arteries of one group of rats and a salt-water solution into the arteries of rats in a control group.
Sarter and his colleagues used the microsphere model in order to look at loss of mental function in a normal, aging brain. Traditional animal models for decreased blood flow involve shutting off a main artery, which produces massive damage throughout the brain.
"That's a pretty brutal model, and it doesn't always reflect the more subtle and limited vascular disorders in the aging brain," Sarter said. "By using microspheres we get a more accurate representation of typical microvascular disorder in the aging brain."
Prior to the injections, the animals had been trained to press a bar for water when they perceived flashes of light, and to press a different bar when they did not. A week after surgery, the animals were subjected to the task again.
The microspheres, by now lodged in the fine endings of the arteries in the rats' brains, impaired the animals' ability to respond correctly to the light trials – their hit rate was nearly half that of the control rats.
"There was an obvious loss of input into the brain's blood vessel system, and the consequences to the rats' ability to pay attention were profound," Sarter said. "Blood supply and nerve cell functions are connected – that's why there is an escalation of mental impairments and, ultimately, dementia after an initial decline in the functions of nerve cells."
The researchers sacrificed the microsphere-treated rats several weeks after surgery in order to look at cortical tissues, where acetylcholine is released. In the cortex, the density of axons that released acetylcholine was strikingly reduced.
"The occurrence of ministrokes and microvascular disorders are significant risk factors for dementia, including Alzheimer's disease," Sarter said. "But our knowledge of what happens after a stroke and during these other processes is very limited. This new model of microsphere-induced decreased blood flow gives us better insight into the consequences of abnormal vascular activity."
This research was supported by Public Health Service grants from the National Institutes of Health.
Contact: Martin Sarter, 614-292 1751; Sarter.2@osu.edu
Written by Holly Wagner, 614-292-8310; Wagner.235@osu.edu