Sex-specific Learning Differences Found in Fragile X Patients, Mouse Model

In females, learning impairments were more intermediate, variable

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Girls and women with fragile X syndrome show different learning impairments relative to boys and men with the disease, a finding that was paralleled in a mouse model of the disease, a study found.

A feature common across both sexes and species was a difficulty in cognitive flexibility, or the ability to adapt to new situations.

“This suggests the promise of using analogous paradigms of cognitive flexibility across species that may speed treatment development to improve lives of individuals with FXS [fragile X syndrome],” the researchers wrote in the study, “Parallel learning and cognitive flexibility impairments between Fmr1 knockout mice and individuals with fragile X syndrome,” which was published in Frontiers in Behavioral Science.

Fragile X is caused by mutations in FMR1, a gene in the X chromosome that’s responsible for producing the FMRP protein, which regulates the production of several other proteins involved in nerve cell communication. Its deficiency leads to the intellectual, behavioral, and learning challenges.

Since males only have one X chromosome (inherited from the mother), those who inherit the mutated FMR1 gene will have more severe disease. Women have two X chromosomes, one from the mother and one from the father, so a healthy FMR1 gene copy can partly compensate for the mutated one.

People with fragile X frequently have difficulties with cognitive flexibility and switching attention between tasks as needed. They often face limitations in daily living and social skills as a result.

There is a “limited understanding of what underlying cognitive processes are altered that contribute to a cognitive flexibility deficit in FXS,” the researchers wrote, adding that knowing this could help in developing treatments.

Despite the extensive use of mouse models to understand molecular and behavioral changes related to fragile X, few cognitive flexibility tests can be employed in both patients and animals. This limits the “probability that treatments found effective in preclinical experiments successfully translate to the clinic,” said a team of researchers in the U.S. who conducted a series of parallel tests in both patients and mice.

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Learning between sexes in patients, mice

The researchers focused on probabilistic reversal learning, the ability to adapt behavior based on changing information. Reversal learning requires a person to suppress a learned response and switch to a different or new, learned response pattern. This type of test lets researchers identify the altered cognitive processes underlying cognitive inflexibility in humans, nonhuman primates, and rodents.

The study included 55 children and adults with a diagnosis of fragile X, among whom 37 (67%) were male. Their ages ranged from 5 to 47. Thirty-four typically developing people matched with patients for age and sex served as controls.

All were asked to first complete a training test before taking the probabilistic reversal learning test. In that test, participants had to select the highlighted image of a cartoon animal from among two otherwise identical pictures. Those who achieved a certain number of consecutive correct answers advanced to the reversal learning test wherein the position of the highlighted drawing would change without warning.

In the training test, boys and men with fragile X required a significantly greater number of trials than the controls to advance to the reversal learning test. No significant group differences were observed for girls and women. Both male and female patients needed significantly more trials than the controls in the reversal learning test.

A reversal learning impairment in girls and women with fragile X was linked to more severe symptoms of irritability, depression, and obsessive-compulsive disorder. In boys and men, it was linked to broader challenges across multiple areas of executive function — cognitive abilities needed for self-control, flexible thinking, and coordinating behavior, emotion, and cognitive capabilities.

Males also “made more perseverative errors than females across groups,” the researchers wrote. Perseverative errors refer to continuing to choose the previously correct response following a change in the position of the correct image.

Results in a mouse model of fragile X

The researchers ran a similar set of tests in a mouse model of fragile X that carries mutations in the Fmr1 gene.

Like the patients, FMRP-deficient male mice were impaired in both training and reversal learning tests compared with healthy mice. In the female mouse model, an impairment was seen only in reversal learning.

Only a subset of male and female mice with fragile X-like disease made more perseverative errors than healthy mice, while both sexes of the mouse model “committed significantly more regressive errors during reversal learning,” the researchers wrote. Regressive errors occur when a subject returns to a previously correct position after having selected a new position correctly.

“In female mice and humans, the probabilistic learning and reversal learning tests showed not only a more intermediate [impairment], but also a more variable [impairment],” the researchers wrote, adding that this is consistent with the inheritance pattern of fragile X.

“The present study is the first of its kind taking a translational approach to characterize learning and cognitive flexibility deficits in both” fragile X patients and mouse model, they wrote.