A new study published in the journal Physiology & Behavior has found that adolescent rats modeled with autism-like symptoms showed significant improvements in brain function and cognitive abilities after regular treadmill exercise. These findings suggest that even low-intensity exercise could offer benefits for individuals with autism spectrum disorder, potentially enhancing cognitive flexibility through changes at the molecular level.
Autism spectrum disorder is a complex condition that affects about 1 in 36 children, impacting their ability to communicate, interact socially, and adapt to changes. Many individuals with autism also struggle with cognitive flexibility, which is the ability to switch between thinking about different concepts or to think about multiple concepts simultaneously. Previous studies have shown that aerobic exercise can improve cognitive function in various neurological conditions, including autism. However, the exact biological processes that drive these improvements are not well understood.
The researchers were particularly interested in the brain-derived neurotrophic factor (BDNF), a protein that supports the survival of existing neurons and encourages the growth of new neurons and synapses. BDNF is crucial for learning and memory and is known to be influenced by physical activity. The study also focused on two other molecules, irisin and interleukin-6 (IL-6), which are produced during exercise and have been linked to brain health. The goal was to see if exercise could regulate these molecules in a way that improves cognitive function in autism-modeled rats.
“Autism spectrum disorder is a prevalent neurodevelopmental disorder and finding ways to regulate brain function to reduce symptoms is important for many individuals and their families,” said study author Bethany Plakke, an assistant professor at Kansas State University. “We hypothesized that exercise may be an additional intervention that could be used to increase levels of BDNF, which is a protein associated with synaptic maintenance and plasticity. Regulating these at the molecular level can lead to improved cognitive outcomes and that is what we observed in our study.”
The researchers used a well-established animal model to simulate autism-like behaviors in rats. They injected pregnant rats with valproic acid (VPA), a substance known to increase the risk of autism-like symptoms in the offspring. The resulting offspring exhibited behaviors and brain characteristics similar to those observed in humans with autism.
Upon reaching adolescence, the rats were divided into groups, with some receiving regular treadmill exercise while others remained sedentary. The exercise regimen consisted of running on a treadmill for 30 minutes a day, five days a week, for four weeks. The intensity of the exercise was low to moderate, making it a manageable routine that could easily be translated into human contexts.
To assess the impact of exercise on cognitive function, the researchers used a set-shifting task, which is analogous to the Wisconsin Card Sorting Test used in humans. This task measures cognitive flexibility by requiring the rats to switch between different types of stimuli (such as odors and digging media) to receive a reward. The number of errors made and the time taken to complete the task were recorded and analyzed.
After the behavioral tests, the researchers examined the rats’ brains to measure the levels of BDNF, irisin, and IL-6 in key regions associated with cognitive function, such as the hippocampus and prefrontal cortex. They also analyzed antioxidant enzymes in the rats’ skeletal muscles, as these are important markers of overall physical health and could provide insights into how exercise affects the body’s resistance to stress.
The study revealed key differences in how exercise affected the rats, depending on their sex and whether they were exposed to VPA. For female rats, exercise had a notably positive impact on cognitive flexibility. The female rats that exercised performed better in the later phases of the set-shifting task, indicating improved cognitive flexibility compared to their sedentary counterparts. This improvement was particularly evident in the final stages of the task, where both control and VPA-exposed females showed a significant reduction in errors after exercise.
In contrast, the male rats showed a more complex response to exercise. While exercise improved performance in some aspects of the set-shifting task, it also appeared to impair performance in the most challenging phase of the task for both control and VPA-exposed males. Interestingly, despite these setbacks, exercised male rats — especially those exposed to VPA — still formed an attentional set, a key marker of cognitive learning. This suggests that while exercise may have introduced some challenges for the males, it also reinforced their ability to learn and adhere to rules during the task.
“We were not expecting exercise to differentially impact males and females,” Plakke told PsyPost. “Our prior work found exercise benefited both sexes. However, in this study we began exercise at a young age, and we hypothesize that in young males there was an interaction where an additional stressor, the exercise, could have reduced benefits cognitively. Other researchers have found stress can impact cognition in young males more than in females.”
On a molecular level, exercise significantly increased the levels of BDNF in the hippocampus of both male and female rats. For the VPA-exposed females, exercise brought BDNF levels up to those of the control group, effectively rescuing the deficits caused by VPA exposure. In males, exercise consistently elevated BDNF levels, regardless of whether they were exposed to VPA or not. These findings suggest that exercise may enhance cognitive function by promoting brain plasticity through increased BDNF expression.
The study also found that exercise influenced the levels of irisin and IL-6 in the rats’ brains. In female rats, exercise decreased irisin levels in control animals but slightly increased them in VPA-exposed animals. In males, exercise increased IL-6 levels in the hippocampus, a response that was observed in both control and VPA-exposed groups. These changes suggest that the relationship between exercise and these molecules may differ between males and females, possibly due to differences in how their bodies and brains respond to physical activity.
Additionally, the researchers observed that exercise improved motor coordination in all rats, as evidenced by better performance on the rotarod test, a standard measure of motor skills. This improvement in motor function was accompanied by increased levels of antioxidant enzymes in the skeletal muscles of VPA-exposed rats, suggesting that exercise not only benefits the brain but also enhances overall physical health.
“Exercise is beneficial for the brain and body,” Plakke said. “Our paper suggests it assists with improving BDNF regulation in the hippocampus as well as improved cognitive performance, even in young animals. It also demonstrates that antioxidants were upregulated in the muscle of the animal model of ASD-phenotypes, even with low intensity exercise, which suggests that for those with ASD physical exercise may assist with cellular regulation of the muscles. Muscular antioxidants released during exercise can also circulate back to the brain and impact brain function.”
The use of an animal model of autism offers several important advantages, particularly when it comes to studying the underlying molecular and cellular mechanisms. These models allow researchers to manipulate and observe specific biological processes in ways that would be ethically or practically impossible in human subjects. For example, by using rodents, scientists can control for environmental variables, apply precise genetic modifications, and directly measure brain activity or molecular changes in specific regions.
However, while animal models provide a powerful tool for understanding the biology of autism, they come with inherent limitations. Rodents, despite their genetic and physiological similarities to humans, have significant differences in brain structure, behavior, and cognitive abilities. These differences mean that findings in animal models may not fully translate to human conditions.
Another caveat to note is that the exercise was forced, rather than voluntary, which could have introduced stress. “We used treadmills which may involve additional stress compared to voluntary wheel running,” Plakke noted. “However, this meant that all animals performed the same amount of exercise daily.”
Nevertheless, the findings provide evidence that even moderate exercise can lead to significant molecular changes in the brain, which in turn can enhance cognitive abilities. Looking forward, these findings could inform the development of targeted exercise-based interventions that may be tailored to specific neurodevelopmental conditions, potentially leading to more personalized and effective treatments for cognitive impairments associated with disorders like autism.
“Our lab is using multiple models of neurodevelopmental disorders to try and understand changes in brain function,” Plakke explained. “We have funded projects examining the changes in prefrontal function that impact cognition and are using different recording techniques to be able to compare the neural signature of the brain between animals and humans (local field potentials). The goal is to understand when the signature is different across various cognitive demands and then test if a treatment can rescue the neural signal.”
The study, “Adolescent treadmill exercise enhances hippocampal brain-derived neurotrophic factor (BDNF) expression and improves cognition in autism-modeled rats,” was authored by Cole King, Liza G. Rogers, Jeremy Jansen, Bhavana Sivayokan, Jenna Neyhard, Ellie Warnes, Stephanie E. Hall, and Bethany Plakke.
