Autism-related Behaviors Are Shaped by Neurons Outside of the Brain

AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE

Lauren Orefice has been named the 2019 grand prize winner of the annual international competition, The Eppendorf and Science Prize for Neurobiology, for research that shows how neurons outside of the brain – those that control the sensation of touch – can alter brain function and shape select behaviors associated with autism spectrum disorders (ASD). Her work in mice demonstrates that these cells, called peripheral somatosensory neurons, may be effective therapeutic targets for improving some ASD-related symptoms.

“Dr. Orefice’s research adds an unexpected novel aspect to the basic scientific understanding of autism, providing a surprising revision of widely-held views that link autism spectrum disorders exclusively to brain function,” said senior Science editor Dr. Peter Stern.

ASD are highly diverse disorders with steadily increasing prevalence; 1 in 59 people in the U.S. are reported to be living with ASD. The disorders are associated with a wide variety of symptoms, including difficulty with social interaction and communication, repetitive behaviors and interests, and abnormal reactivity to sensory stimuli, such as light, sound, pressure and heat. Patients with ASD are also often diagnosed with anxiety disorders, gastrointestinal problems, and sleep disturbances.

Because the genetics and behaviors underlying ASD are so varied and complex, finding consistent links among all these components remains a challenge. To date, the wide variety of ASD-related symptoms has been largely attributed to dysfunctional neuronal activity in the brain. In her prize-winning essay, “Outside-in: Rethinking the etiology of autism spectrum disorders,” Orefice suggests that this view is incomplete.

One of the more overlooked, yet frequently observed, symptoms in patients with ASD is over-reactivity to touch, whereby a gentle breeze or hug could be unpleasant or possibly painful. The first steps in touch perception occur in peripheral somatosensory neurons, which receive inputs from the whole body. Thus, Orefice, her colleague David Ginty, and their team reasoned that exploring somatosensory neuron function throughout the nervous system, even outside the brain, might lead to promising, new insights into the understanding of ASD.

Using mouse models for ASD, the researchers assessed sensitivity to gentle touch. Somatosensory networks have been well-characterized in mice, so Orefice, Ginty and their colleagues took advantage of this “great genetic tool box” to search for cells in which ASD-related genes Mecp2, Gabrb3, and Shank3 might affect sensitivity to touch.

Deleting ASD-related genes in different somatosensory cell types throughout the nervous system, Orefice and her colleagues found that the loss of these genes in brain-residing excitatory neurons produced no major symptoms associated with ASD. Rather, genetic mutations in neurons that receive light touch signals from the skin correlated with increased sensitivity to touch.

“We were initially quite surprised by the finding that peripheral sensory neuron dysfunction contributes to abnormal touch behaviors in ASD mice, “said Orefice.

In addition to demonstrating over-reactivity to touch, mice lacking Mecp2, Gabrb3, or Shank3 in peripheral sensory neurons exhibited social impairments and anxiety-like behaviors reminiscent of those observed in patients with ASD. Restoring these genes selectively in peripheral neurons normalized some – but not all – ASD-associated symptoms in the mice, including reactivity to touch, anxiety-like behaviors, and select social behaviors.

“The importance of peripheral neurons for touch processing is interesting, but the general behaviors of the conditional mutant mice were even more remarkable,” said Orefice in her essay. Based on these findings, she posed the question: how could genetic mutations in neurons outside of the brain affect social impairments and anxiety-like behaviors that are thought to be controlled by neurons inside the brain?

Decades of research indicate that sensory input guides brain development and behavior, said Orefice. She and her colleagues postulated that if sensory inputs were altered through mutations in peripheral sensory neurons, this might alter developmental and functional properties of neuronal circuits in brain. Therefore, improving peripheral neuron function to reduce sensitivity to touch might also help relieve other ASD-related symptoms.

Testing this hypothesis in six different ASD mouse models, Orefice et al. found augmenting signals that inhibit some of the sensory activity in peripheral neurons diminished hypersensitivity to touch. In addition, long-term application of this treatment in mice with Mecp2 and Shank3 mutations led to major improvements in brain development, anxiety-like behaviors and some social impairments.

Importantly, this treatment did not cross the blood-brain barrier, lowering the chance of triggering harmful side effects ascribed to some drugs that act on the brain.

“I am really excited about our findings and the directions my lab is now exploring,” said Orefice.

She hopes these findings will lead to the development of a new class of compounds that are chemically altered to act selectively on peripheral somatosensory neurons – reducing their excitability – while sparing the brain.

“We will need to determine which people with ASD exhibit over-reactivity to light touch stimuli and therefore who would benefit from this type of treatment,” she said.

Additional areas of interest for the Orefice lab include investigating how the activity of somatosensory neurons in other areas of the body, like the gastrointestinal tract, are affected in ASD. Her lab also seeks to pinpoint mechanisms through which altered sensory input due to peripheral sensory neuron dysfunction impacts brain development and complex behaviors.

Orefice and the following finalists will be recognized at a prize ceremony on October 20, 2019 starting 6:30 pm at the St. Jane Hotel in Chicago.

2019 Grand Prize Winner

Lauren Orefice, for her essay, “Outside-in: Rethinking the etiology of autism spectrum disorders.” Orefice received her B.S. in Biology from Boston College and her Ph.D. in Neuroscience from Georgetown University. Following her postdoctoral work at Harvard Medical School, Orefice started as an assistant professor in the department of molecular biology at Massachusetts General Hospital and the department of genetics at Harvard Medical School in 2019. Her lab studies the development and function of somatosensory circuits, and how somatosensation is altered in developmental disorders.

Finalist András Szőnyi, for his essay “Conducting memory formation: The nucleus incertus in the brainstem orchestrates the formation of contextual memories.” Szőnyi received undergraduate degrees in medicine and a Ph.D. in neurosciences from the Semmelweis University in Budapest, Hungary. He performed research in the Institute of Experimental Medicine of the Hungarian Academy of Sciences. Currently, Szőnyi is a postdoctoral fellow in the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. He studies the cellular mechanisms of learning and memory formation in mice using in vivo imaging and optogenetics.

Finalist Zvonimir Vrselja, for his essay “Destined for destruction? Restoring brain circulation and cell functions after prolonged global anoxia.” Vrselja received his MD and Ph.D. from J.J. Strossmayer University in Croatia. After completing his graduate education, he started his postdoctoral training at Yale University in New Haven, CT. He currently holds the position of associate research scientist in the Sestan Laboratory at the Yale School of Medicine. His research focuses on the development of a system that preserves global anatomical organization, as well as cellular organization; attenuates cell death; and restores neuronal, glial, and vascular functionality, along with global metabolism, in isolated large mammalian brains several hours after death.

For the full text of finalist essays and for information about applying for next year’s awards, see the Science Web site at http://www.sciencemag.org/prizes/eppendorf

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