Researchers at Johns Hopkins Medicine report that new experiments in genetically engineered mice have found clear associations between a range of autism types and abnormalities in brain cells, the chemical output of which evokes platonic (non-sexual) feelings of love and sociability.
The results, the researchers say, could ultimately fuel the development of autism therapies that target disease symptoms triggered by abnormalities in parvocellular oxytocin neurons, which are brain cells in the hypothalamus of mammals.
A report of the experiments was published online in Neuron on October 27th.
Researchers tracked evidence of the relationship based on long-known differences in the shape and symptoms of autism spectrum disorders and because those with Fragile X – a hereditary disorder that affects one in 4,000 men and one in 6,000 women – are often characterized by the Inability to form close social bonds.
Autism is defined by impaired social behavior, but not all social behaviors are created equal. People with autism generally have less difficulty forming very close family ties than they do with friendships. Our experiments provide evidence that these two types of affections are encoded by different types of oxytocin neurons and that the disruption of one of these types of neurons is responsible for the characteristic social impairments that occur in autism. ”
Dr. med. Gül Dölen, Associate Professor of Neuroscience, Johns Hopkins University Medical School
For more than a century, says Dölen, scientists have known that there are two types of neurons in the hypothalamus. The neurons release what is known as the “love hormone” oxytocin, which causes contractions during labor, reduces stress, and promotes bonding between animals between species of mammals, including humans.
A magnocellular oxytocin neuron, a type of oxytocin-releasing neuron, releases large amounts of oxytocin to the brain and body – up to 500 times or more than parvocellular oxytocin neurons, which limit their scope and avoid flooding the neuron with the body all consuming feelings of love.
As the name suggests, oxytocin magnocellular neurons are larger than other neurons and can send their arm-like axons across the blood-brain barrier. Magnocellular oxytocin neurons stimulate childlike love – what Dölen calls “crazy love” – and the bond between infants and mothers and between sexual partners.
Dölen’s research shows that parvocellular oxytocin neurons, which come from the Greek word “parvo” or “small”, also code for social behavior, but code a different type than the magnocellular neurons.
While magnocellular oxytocin neurons encode social behaviors related to reproduction (couple bonding and parental bonding), parvocellular oxytocin neurons encode social behaviors related to what Dölen calls “love in measure,” or the platonic love that is common to communities ( Friends and colleagues) is important.
In order to investigate whether and how symptoms of autism are linked to disorders in one or both of the magnocellular and parvocellular neurons, Dölen and her team first genetically engineered mice that shine a fluorescent light in all of the oxytocin neurons, Magno and Parvo.
Knowing that magnocellular neurons project their axons and chemicals across the blood-brain barrier, the research team used dyes that stay within the barrier to mark only the parvocellular neurons – which are rarer, harder to see and smaller.
Next, Dölen enlisted the help of Johns Hopkins scientist Loyal Goff, who is an expert in mapping the genetic profile of individual cells. The technique, known as single cell sequencing, specifically reads a single cell’s RNA – a genetic relative of DNA – which tells how the cell’s genetic code is read and which proteins are produced. The way our genetic code is read distinguishes one cell type from another.
“This study is a comprehensive characterization of two types of closely related neurons that are involved in the regulation of social behavior,” said Goff, assistant professor of genetic medicine at the Johns Hopkins University School of Medicine.
“One of the things that make this study unique is the multimodal aspect of this characterization, which relates anatomical, morphological, electrophysiological, transcriptional, genetic, and behavioral traits to fully define the relevant and important differences between these two types of neurons . “”
The research team used single cell sequencing and other gene tracking tools and techniques to ensure that the subpopulations of magnocellular and parvocellular neurons were actually different so that they could genetically alter each group to see if a change would induce autism-like behavior in mice.
What the researchers measured was how much the mice liked their social interactions and how much they preferred things associated with those social interactions (like bedding).
To build a model of autism in mice, the scientists turned to the FMR1 gene linked to Fragile X, an inherited condition characterized by intellectual disability but also one of the most commonly identified causes of autism and in about five percent of people with the disease occurs.
In humans, the FMR1 gene is silenced by a cellular process that involves adding chemicals called methyl groups to the gene. The same process does not take place in mice. To replicate the FMR1 genetic anomaly, the scientists genetically engineered the mice so that they did not have a functioning FMR1 gene either in the entire brain or only in parvocellular neurons.
Researchers investigated how mice lacking FMR1 appreciated the rewards of social bonding with an adult female mouse serving as a surrogate parent. These mice learned to like bedding associated with the surrogate parent, but not bedding associated with social interactions with their peers – evidence that mutations in genes that cause autism selectively disrupt platonic love but childish love Save love.
When the scientists deleted the FMR1 gene only in parvocellular cells and not in magnocellular cells, the mice reacted in exactly the same way: intact affinity for things associated with their surrogate parent versus things associated with peer mice. The scientists did not find such a preference in mice lacking FMR1 in magnocellular oxytocin cells.
In another series of experiments to determine the specificity of their results with the oxytocin-producing neurons, the scientists examined how certain genes associated with risk for autism switched on or off between the two types of oxytocin neurons or were expressed.
They found that significantly more autism risk genes in parvocellular neurons had higher expression levels than in magnocellular neurons. However, when the scientists examined genes for schizophrenia, Alzheimer’s disease, and diabetes, there were no such differences in gene expression between the two types of oxytocin neurons.
“This shows us that the difference we see between the two types of oxytocin neurons is related to the disease that is characterized by impaired social behavior, but not to diseases in which that behavior is not a defining symptom,” says Dölen.
She also notes, “What can happen in the brain is that while all brain cells can carry a certain mutation associated with autism, some neurons are more prone to symptoms associated with social attachment.”
Dölen plans to conduct similar studies on genes associated with other types of autism. She says her work may suggest that drugs currently being tested for autism, such as intranasal oxytocin, may prove ineffective as the treatments target magnocellular neurons, which the new study says is not central to the disease.
Instead, she says, her evidence suggests that parvocellular oxytocin neurons should be the focus of drug development for autism.
Lewis, EM, et al. (2020) Parallel circuits for processing social information are affected differently in autism. Neuron. doi.org/10.1016/j.neuron.2020.10.002.
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