All else being equal, humans and other animals tend to interact with their fellow creatures more than they investigate inanimate objects. This preference for social interactions is so crucial for survival that its absence is considered a sign of illness, as in the case of autism spectrum disorders and Rett syndrome.
A team of researchers from the George Washington University (GW) has now shown how a particular part of the brain called the medial prefrontal cortex (mPFC) enables mice to choose to interact with a fellow mouse instead of an inanimate object. Stimulating this part of the brain in a mouse model of Rett syndrome restores their interest in social engagement.
“Social interactions are incredibly complex and difficult to study,” said Hui Lu, PhD, assistant professor of pharmacology and physiology at the GW School of Medicine and Health Sciences (SMHS) and corresponding author of the study. “For a long time, it has been thought that children with autism spectrum disorders display social avoidance because they seem more interested in objects than in faces or responding to social cues. This was thought to be the case with girls with Rett syndrome as well, who seem to lose interest in interacting with their loved ones when the disease sets in. Our results suggest that children with Rett are not actually avoiding interaction, but rather that they can no longer distinguish social from nonsocial cues.”
Part of the tragedy of Rett syndrome, which tends to affect girls, Lu adds, is that the children develop normally for the first two years of life. They then undergo a period of regression during which they lose all the motor and cognitive skills they have achieved, including their enjoyment of interacting with their parents. A loss-of-function mutation in the Mecp2 gene causes the disease by changing the expression of thousands of other genes, but little is known about what goes wrong in the brain at the level of neural circuits.
The research team, which included faculty from GW SMHS, the GW School of Engineering and Applied Science, the GW Columbian College of Arts and Sciences, and a faculty member from the University of Virginia, used in vivo calcium imaging to monitor the activity of neurons in the PFC, which processes many types of information important for social behavior.
The team found that mPFC excitatory neurons of wild type, or “normal,” mice generate different patterns of neuronal coactivity to distinguish social from nonsocial cues. The mPFC of Rett mice, however, tended to respond very little to any type of stimulus, even though their background level of activity was similar to that of wild-type mice. Taking their cue from how the olfactory system distinguishes different odors, the researchers hypothesized that this lack of response restricted the brain’s ability to create distinct patterns of coactivity for different stimuli. They then determined that stimulating the mPFC in Rett mice restored social preference by increasing the dynamic range of the neurons, which enabled them to create distinct coactivity patterns for social and nonsocial stimuli.
“Our findings indicated that a loss of social preference in mice with this genetic mutation is due to the inability to distinguish different types of stimuli rather than true social avoidance,” Lu said. “This means that in Rett syndrome, and possibly other autism spectrum disorders, the lack of interest in social interaction is not because of anxiety or avoidance. By stimulating the medial prefrontal cortex of the brain, we can potentially improve the social interactions of not just Rett syndrome patients, but also those with autism-related disorders.”
The research, “Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2,” appears in the July 2022 edition of Nature Communications.
