Autism mouse fashions cluster by mind exercise sample | Spectrum
Talk time: fMRI images of several autism mouse models show different communication patterns between brain regions.
Courtesy of Alessandro Gozzi
Brain scans from 16 mouse models of autism reveal at least four different patterns of brain activity, a new study suggests. The results again support the popular notion that autism is associated with a number of brain “signatures”.
Tell-tale neural signatures of autism have long proven elusive, with functional magnetic resonance imaging (fMRI) and other brain-scanning technologies being to blame for scattered and inconsistent results.
“A big question is whether there is a single signature of dysfunction in the brain of people with autism. And many people think that’s something that has to be there, ”says study researcher Alessandro Gozzi, senior researcher at the Istituto Italiano di Tecnologia in Rovereto, Italy. “If we haven’t found it yet, the method must be to blame: fMRI.” The method measures small changes in blood flow and oxygen supply as an indirect measure of brain activity.
For the new study, published in Molecular Psychiatry in August, Gozzi and his colleagues used fMRI to examine the connectivity patterns of the brain – or which regions of the brain “talk” to each other and to what extent. Regions of the brain are considered to be communicating when they have synchronous vibrations in the blood flow.
To address the issue of reproducibility in fMRI, the researchers performed their analysis on mice, anesthetized the animals, and fixed their heads to prevent any movement that could disrupt the brain signals. “We have moved to a model organism in which we can control down to the smallest detail many of the factors that are considered to be the basis of this variability, this unreliability of the imaging,” says Gozzi.
The 16 mouse models can be divided into four groups based on the patterns of brain activity, the analysis showed. For example, one group shows increased connectivity between areas in the prefrontal cortex and the amygdala, social and emotional regions of the brain, respectively; another group has increased connectivity between the hippocampus and the ventral orbital cortex, regions involved in memory and higher cognitive functions.
“I think we know that autism is very heterogeneous from a behavioral point of view,” says Kaustubh Supekar, clinical assistant professor of psychiatry and behavioral science at Stanford University in California, who was not involved in the study. “To expect that we would find a common signature for such a heterogeneous state was a kind of pipe dream.”
Clustered Connections:
Gozzi and his colleagues photographed 350 animals, including controls, and approximately the same number of each of the 16 autism mouse models at locations in Italy and Switzerland: 13 models with autism-associated mutations, including in the SHANK3, FMR1 or MECP2 genes; Mice deficient in microglia, immune cells that form neural connections; Mice exposed prenatally to the immune signal molecule IL-6; and an inbred strain called BTBR.
A machine learning model trained on the fMRI data grouped these results into four groups. Mice with mutations in the genes CHD8 or SYN2, those with deletions in the chromosomal region 16p11.2 and the BTBR and IL6 models all have reduced neuronal signal transmission between the cortex, striatum and inferior colliculus, but increased signals between the ventral orbital cortex and the hippocampus.
In contrast, mice with mutations in SHANK3, CNTNAP2 and SGSH have reduced activity between the hippocampus and insula and a moderate increase between the nucleus accumbens and hypothalamus.
The other mouse models, such as those with mutations in CDKL5 or MECP2, or animals with missing microglia, were grouped into two additional groups with completely different neuronal activity patterns.
Clinical start:
Although it focused on mice, the new study could have clinical implications, researchers say.
“This clustering of different subsets of animal models is really a first step towards understanding what to expect in humans,” says Itamar Kahn, associate professor of neuroscience at Columbia University, who was not involved in the study.
For example, humans and mice harboring a 16p11.2 deletion have similar changes in brain connectivity, as Gozzi’s group previously demonstrated.
But Gozzi’s use of anesthesia could be problematic, says Vinod Menon, a professor of psychiatry and behavioral science at Stanford University who wasn’t involved in the study.
“The anesthetized brain is very different from an awake, behaving brain,” he says. “There’s no question that this study will have a huge impact, and I think it’s an important step, but it will be interesting to see what happens in the case of non-anesthetized mice as well.”
For future studies, Gozzi plans to triple the number of autism animal models scanned, which could lead to additional “clusters” of brain connectivity.
“We want at least 50. to scan [mouse models] start talking about how different mutations can be grouped based on connectivity, ”he says.
Scanning mice with one mutation each may not accurately reflect the complexity of autism. Many autistic people carry numerous mutations that contribute to their condition.
“We know that these genes don’t work in isolation,” says Supekar. “Then it becomes an exponentially complex thing where you have to build models with many genes turned off at the same time.”
Quote this article: https://doi.org/10.53053/JUPD6575
