Researchers link neuronal hyperactivity and broader tuning with altered sound processing

People with autism spectrum disorders commonly have difficulty processing sensory information, which can make busy, bright or loud settings – such as schools, airports and restaurants – stressful or even painful. The neurological causes for altered sound processing are complex, and researchers are interested in better understanding them to make life better for people with autism.

In a study that combines behavioral tests, computer models and electrophysiological recordings of neuron activity, researchers have found that hyperactivity of neurons in the auditory cortex and the reaction of these neurons to an unusually broad range of frequencies contribute to this altered sound processing in rat models.

“One of the things we thought wasn’t being looked at enough was this idea of sensory discrimination: being able to distinguish between different features in our environment,” said Benjamin Auerbach, a professor of molecular and integrative physiology at the University of Illinois Urbana-Champaign. “That’s really important, especially in real-world conditions where you have a lot of competing info coming in at once and you need to be able to parse that information out and make sense of it. If you have degraded feature discrimination, that can make complex or cluttered sensory environments really overwhelming.”

Fragile X syndrome is the leading inherited cause of autism in humans, in which a gene called FMR1 is deactivated. Therefore, to represent autism in a laboratory setting, the researchers used rats disabled FMR1 gene, called knockout rats.

Auerbach and Walker Gauthier, a neuroscience graduate student and lead author of this study, specifically chose to look at frequency discrimination: how the brain can tell the difference between the pitches of different sounds.

The FMR1 knockout rats participated in a series of behavioral trials to determine how well they could differentiate between two frequencies compared to rats which still had their FMR1 gene enabled (called wild-type rats). A range of frequencies were played to the rats, but the rats were trained to only react to a specific target frequency while inhibiting their response to other frequency tones.

When the played tone was very far from the target frequency, all rats performed similarly: neither group reacted to the sound. Similarly, when the played tone was very close to the target frequency, rats from both groups falsely identified the tone as correct. Only in the middle range – when the played tone was one-third to two-thirds of an octave away from the target frequency – did the behavior of the two groups diverge. The FMR1 knockout rats had a much harder time identifying that the played tone was not actually the target tone.

To further explore why this was happening, the researchers recorded the activity of two key brain hubs essential for the processing of auditory information: the auditory cortex and inferior colliculus. While the inferior colliculus behaved similarly for both groups of rats, the activity of the auditory cortex differed.

Walker Gauthier.

“The knockout rats exhibit increased spontaneous activity: how much the neurons fire when no sound is being played,” Gauthier said. “And when I played a sound, there was a bigger response to that sound in the knockout rats as well, but only in the cortex.”

Differentiating frequency is an essential part of the auditory system, and different auditory neurons are tuned to different frequencies. While usually, a given neuron only responds when exposed to a narrow range of frequencies, the researchers found that auditory cortical neurons in the FMR1 knockout rats responded to an unexpectedly wide range instead. This explains why they had a more difficult time telling frequencies apart.

“If we have broader tuning in the cortex, that means more neurons are responding to more sounds,” Gauthier said. “It makes sense that with two sounds that are close together, a person might not be able to tell the difference between the two because their neurons are responding to more sounds in general.”

To test whether this cortical hyperactivity was responsible for the FMR1 rats’ difficulty in telling sounds apart, Auerbach and Gauthier used their measurements of cortical neuron activity to create a computer model of the brain’s activity. Then, they used this model to replicate the frequency identification experiment they had conducted with rats. If the model brain was adjusted such that the cortical neurons reacted to the broad range of frequencies that the FMR1 knockout rats’ neurons did, would the computer behave as the FMR1 knockout rats did in the experiment?

When tested, the model indeed behaved as the rats did in the behavior experiment, supporting that the observed altered sound processing is linked to the neurons’ broad tuning.

Generally, this study suggests that the brain has to balance sensitivity to sounds with the ability to distinguish between sounds. With FXS, sensitivity is highly weighted, sacrificing sound discrimination. 

This also explains the results from a previous study, which led to the development of this one, in which tones were played to wild-type and FMR1 knockout rats who were trained to react to the sound. The FMR1 knockout rats reacted quicker than their wild-type counterparts: a result that suggested that they were more confident that they heard the tones, potentially because they perceived them as louder than the wild-type rats did. This was especially true with broad bandwidth sound: when multiple sound frequencies were played simultaneously.

“Our results from our recent study can actually explain that result, because if their neurons are more broadly tuned, as you increase the bandwidth of the sound, you’re going to recruit more neurons in the brain of the FMR1 knockout animals compared to wild-type animals,” Auerbach said. “That can make those sounds be perceived as louder because you have a larger population of cells being activated.”

In the future, the researchers plan to conduct studies to determine whether these results also apply to other genetic factors correlated with ASD. They also want to look closer at the cortex, to further explore what is causing the shift towards increased sound sensitivity on the neural level.