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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    092—Associative, Non-Associative, and Skill Learning

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    92.05: Voluntary exercise or manipulation of HIF-1α expression increases hippocampal capillary density and promotes behavioral flexibility in adult rats

    Location: Halls B-H

    Psychology, Univ. of Wisconsin - Milwaukee, Milwaukee, WI

    Abstract Body: In addition to structural and cellular changes, improved cognitive performance is another way in which exercise affects the brain. In rodent models, these exercise-induced improvements in behavioral performance have previously been shown to be mediated, at least partially, by the growth of new capillaries from preexisting ones (angiogenesis); blocking angiogenesis in exercising animals resulted in a severe learning deficit in the Morris Water Maze (MWM), a spatial learning task. Increases in the expression of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) have also been shown to increase capillary density following exposure to hypoxia, or during ischemia. Furthermore, our lab has recently shown that HIF-1α is rapidly upregulated in the hippocampus of adult rats in response to a single bout of forced exercise. Therefore, it is possible that HIF-1α is a mediator of exercise-induced angiogenesis as well as exercise-induced cognitive enhancement. To test this hypothesis, we measured HIF-1α protein expression and angiogenesis in five groups of animals: a voluntary exercise (VX) group, a forced exercise (FX) group, an inactive control (IC) group, a group treated with the HIF-1α agonist dimethyloxalylglycine (DMOG), and a vehicle-treated (VEH) group. We also trained animals in a Morris Water Maze (MWM) paradigm that assessed acquisition, reacquisition, and retention. We found significantly increased HIF-1α expression in area CA1 of the hippocampus in VX, FX, and VEH animals, and significantly increased CA1 capillary density in VX, DMOG, and IC animals. During the acquisition phase of the MWM, we found that VX, DMOG, and IC animals were significantly faster to find the hidden platform on the first day of training compared to FX animals. Furthermore, both exercising groups and the drug-treated group were significantly more successful in finding the hidden platform on the first day of reacquisition training. Compared to exercising and DMOG-treated animals, IC and VEH animals spent the most time in the initial training quadrant, suggesting significant behavioral perseveration. These findings indicate that voluntary exercise and manipulation of HIF-1α expression result in increases in capillary density and in behavioral flexibility. Therefore, it is possible that HIF-1α serves as a mediator of exercise-induced improvements in cognitive performance, a process that appears to operate by way of increases in capillary density. Because exercise has been shown to be neuroprotective, this research is of potential interest in investigations of ischemia, brain injury, and neurodegeneration.

    Lay Language Summary: Our research shows that exercise or treatment with a drug that increases a molecule also increased following stroke or low oxygen conditions (hypoxia) results in improved performance in a spatial learning task in rats.
    A great deal of research has shown that exercise causes significant changes in brain anatomy. In addition, engaging in physical activity has been shown to result in improved cognitive performance in human and non-human animals. Of relevance to clinical populations, engaging in aerobic exercise has been shown to improve the prognosis of victims of brain injury and stroke. It is important to determine the mechanisms by which exercise causes these changes in brain structure and cognitive performance in order to develop novel therapies that may be useful to both clinical and non-clinical populations.
    Interestingly, some of the brain’s responses to stroke and exercise are similar. For example, both aerobic exercise and stroke cause the growth of new blood vessels in the brain, a process known as angiogenesis. The addition of new blood vessels to the preexisting network of capillaries has been linked to improved learning and memory performance. Additionally, an important growth factor - a molecule that aids in brain development and recovery from injury - called the hypoxia-inducible factor 1 alpha (HIF-1α), is increased following exercise and stroke and induces the growth of new blood vessels. A previous study has shown that increasing this growth factor resulted in better memory during a conditioning task. Furthermore, because previous research has established that exercise results in improved performance in cognitive tasks, we tested whether treatment with a drug that increases HIF-1α would result in similar improvements in cognitive performance as exercise.
    To test this, we exposed adult rats to one of five conditions: voluntary exercise, forced exercise, drug-treatment, placebo drug treatment, and a sedentary control condition. We then trained animals in a spatial navigation task called the Morris Water Maze, where the animal must learn to locate a hidden platform in a pool of water using external visual cues. This task includes three different phases of training: acquisition, which tests how efficiently the animal learns the location of the hidden platform; reacquisition, which tests whether the animal can adjust its learning strategy when the platform is moved to the opposite quadrant of the pool; and retention, during which the platform is removed from the pool and tests whether or not the animal remembers the most recent platform location after a period of no training.
    We found that animals in the voluntary exercise condition and animals treated with the drug had the greatest amount of blood vessels in the brain, and these animals learned the task most efficiently. Furthermore, both groups of exercising animals and drug-treated animals performed better than sedentary control animals during the reacquisition phase indicating that animals had adapted to the change in platform location and were still able to successfully complete the task. Finally, unlike placebo-treated and sedentary animals, exercising and drug-treated animals spent the least amount of time in the previously rewarded location indicating a greater degree of behavioral flexibility.
    Our results indicate that the molecule HIF-1α may be a mediator of exercise-induced improvements in cognitive performance, and that these behavioral improvements may operate by way of increases in blood vessel density. Because exercise has been shown to be neuroprotective, this research is of potential interest in investigations of ischemia, brain injury, and neurodegeneration.