UF Scripps researchers’ work sheds new light on relationship between brain structure and behavior in preclinical model of autism

Pten haploinsufficient mice have abnormal rates of growth across brain regions during development. Some regions — including those involved in sensory processing — have relative overgrowth (shown in red) while others relative undergrowth (shown in blue).For people with autism, overstimulating sensory experiences such as noise can have a profound effect on their lives. Now, a group of scientists at UF Scripps Biomedical Research has shed new light on brain development that can lead to autism-related sensory processing disorders.

The breakthrough is one of the first uses of structural brain imaging to reveal a previously unknown autism-related behavioral deficit, said Damon T. Page, Ph.D., an associate professor in the department of neuroscience. Page and his colleagues used magnetic resonance imaging, or MRI, to assess brain size and development in mice carrying a mutation in an autism-risk gene. The findings were published recently in the journal iScience.

The lower back part of the brain, known as the hindbrain, is crucial for sound and other sensory processing in both mice and humans. Mice with disproportionately overgrown hindbrains were more likely to be startled by noises during lab experiments, the researchers found.

“We wanted to see if we could use MRI, which reveals deviations from normal growth patterns, to predict behavioral deficits that may be relevant for autism,” Page said.

To do that, the researchers captured brain images of newborn and mature mice of both genders. The mice were also put through a series of sensory-related tests, including being exposed to sounds of various levels. Those with Pten haploinsufficiency, a genetic mutation that models autism and brain overgrowth in humans, were notably less startled by high-intensity noises. The researchers also tested the mice for pre-pulse inhibition, the ability of a low-intensity stimulus to diminish the startle response from louder noises, and found impairments. The brain regions with the largest overgrowth are associated with sensory processing issues in both sexes of mice, the researchers concluded.

To learn more about the association between brain overgrowth and abnormal behaviors, they also “mapped” behaviors onto specific brain regions. That allowed them to predict behaviors that are most often associated with relatively enlarged brain regions.

In the mice, the overgrown regions of the brain were more likely to be associated with behavioral changes than the undergrown brain areas, said Amy Clipperton-Allen, Ph.D., a staff scientist in Page’s lab and a co-author of the paper. The apparent relationship between increased brain volume and sensory-associated behaviors in both genders of mice suggests that enlargement of certain brain areas leads to the most profound effects, she said.

Page said the findings are meant to do more than just confirm symptoms of autism. By using MRI, the intent is to predict novel symptoms even before they appear as part of a formal diagnosis. Experts often call it the “cascading effects hypothesis” — the idea that sensory-sensitivity issues precede the more apparent social and behavioral deficits of autism.

“It remains to be seen how this translates into the human clinical population. But this is also a means of making novel predictions about the conditions that give rise to autism,” Page said.

While the findings will not apply to all forms of autism, Page said it has the potential to benefit those within a specific genetic population. The current findings will help to inform relevant preclinical trials of drugs that could potentially block the emergence of symptoms or reverse them once they have occurred.

The findings suggest that particular attention should be paid to sensory behavior in children with enlarged brains. Those who are showing sensory deficits may be more likely to subsequently display autism spectrum disorder and associated social impairments, Clipperton-Allen said. 

Research funding was provided by the National Institutes of Health, Nancy Lurie Marks, the Elise M. Besthoff Charitable Foundation and the Academic Year Research Internship for Undergraduates.

Media contact: Doug Bennett at dougbennett@ufl.edu or 352-265-9400

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Doug Bennett

Science Writer, Editor

Doug Bennett joined the UF Health staff in January 2015 as a science writer and editor. His topic areas include anatomy; biochemistry and molecular biology; molecular genetics and microbiology; pathology,...Read More