New autism research projects represent a broad range of approaches to achieving a shared goal | By The Digital Insider

From studies of the connections between neurons to interactions between the nervous and immune systems to the complex ways in which people understand not just language, but also the unspoken nuances of conversation, new research projects at MIT supported by the Simons Center for the Social Brain are bringing a rich diversity of perspectives to advancing the field’s understanding of autism.

As six speakers lined up to describe their projects at a Simons Center symposium Nov. 15, MIT School of Science dean Nergis Mavalvala articulated what they were all striving for: “Ultimately, we want to seek understanding — not just the type that tells us how physiological differences in the inner workings of the brain produce differences in behavior and cognition, but also the kind of understanding that improves inclusion and quality of life for people living with autism spectrum disorders.”

Simons Center director Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences (BCS), said that even though the field still lacks mechanism-based treatments or reliable biomarkers for autism spectrum disorders, he is optimistic about the discoveries and new research MIT has been able to contribute. MIT research has led to five clinical trials so far, and he praised the potential for future discovery, for instance in the projects showcased at the symposium.

“We are, I believe, at a frontier — at a moment where a lot of basic science is coming together with the vision that we could use that science for the betterment of people,” Sur said.

The Simons Center funds that basic science research in two main ways that each encourage collaboration, Sur said: large-scale projects led by faculty members across several labs, and fellowships for postdocs who are mentored by two faculty members, thereby bringing together two labs. The symposium featured talks and panel discussions by faculty and fellows leading new research.

In her remarks, Associate Professor Gloria Choi of The Picower Institute and BCS department described her collaboration’s efforts to explore the possibility of developing an autism therapy using the immune system. Previous research in mice by Choi and collaborator Jun Huh of Harvard Medical School has shown that injection of the immune system signaling molecule IL-17a into a particular region of the brain’s cortex can reduce neural hyperactivity and resulting differences in social and repetitive behaviors seen in autism model mice compared to non-autism models. Now Choi’s team is working on various ways to induce the immune system to target the cytokine to the brain by less invasive means than direct injection. One way under investigation, for example, is increasing the population of immune cells that produce IL-17a in the meningeal membranes that surround the brain.

Gloria Choi describes her team's work to develop a potential immunotherapy for autism.

Photo: David Orenstein/Picower Institute

In a different vein, Associate Professor Ev Fedorenko of The McGovern Institute for Brain Research and BCS is leading a seven-lab collaboration aimed at understanding the cognitive and neural infrastructure that enables people to engage in conversation, which involves not only the language spoken but also facial expressions, tone of voice, and social context. Critical to this effort, she said, is going beyond previous work that studied each related brain area in isolation to understand the capability as a unified whole. A key insight, she said, is that they are all nearby each other in the lateral temporal cortex.

“Going beyond these individual components we can start asking big questions like, what are the broad organizing principles of this part of the brain?,” Fedorenko said. “Why does it have this particular arrangement of areas, and how do these work together to exchange information to create the unified percept of another individual we’re interacting with?”

While Choi and Fedorenko are looking at factors that account for differences in social behavior in autism, Picower Professor Earl K. Miller of The Picower Institute and BCS is leading a project that focuses on another phenomenon: the feeling of sensory overload that many autistic people experience. Research in Miller’s lab has shown that the brain’s ability to make predictions about sensory stimuli, which is critical to filtering out mundane signals so attention can be focused on new ones, depends on a cortex-wide coordination of the activity of millions of neurons implemented by high frequency “gamma” brain waves and lower-frequency “beta” waves. Working with animal models and human volunteers at Boston Children’s Hospital (BCH), Miller said his team is testing the idea that there may be a key difference in these brain wave dynamics in the autistic brain that could be addressed with closed-loop brain wave stimulation technology.

Simons postdoc Lukas Vogelsang, who is based in BCS Professor Pawan Sinha’s lab, is looking at potential differences in prediction between autistic and non-autistic individuals in a different way: through experiments with volunteers that aim to tease out how these differences are manifest in behavior. For instance, he’s finding that in at least one prediction task that requires participants to discern the probability of an event from provided cues, autistic people exhibit lower performance levels and undervalue the predictive significance of the cues, while non-autistic people slightly overvalue it. Vogelsang is co-advised by BCH researcher and Harvard Medical School Professor Charles Nelson.

Simons Center postdoc Chhavi Sood (with microphone) answers an audience question while fellow panelists Lace Riggs (left) and Lukas Vogelsang and moderator Micheael Segel of Harvard University (right), listen.

Photo: David Orenstein/Picower Institute

Fundamentally, the broad-scale behaviors that emerge from coordinated brain-wide neural activity begins with the molecular details of how neurons connect with each other at circuit junctions called synapses. In her research based in The Picower Institute lab of Menicon Professor Troy Littleton, Simons postdoc Chhavi Sood is using the genetically manipulable model of the fruit fly to investigate how mutations in the autism-associated protein FMRP may alter the expression of molecular gates regulating ion exchange at the synapse , which would in turn affect how frequently and strongly a pre-synaptic neuron excites a post-synaptic one. The differences she is investigating may be a molecular mechanism underlying neural hyperexcitability in fragile X syndrome, a profound autism spectrum disorder.

In her talk, Simons postdoc Lace Riggs, based in The McGovern Institute lab of Poitras Professor of Neuroscience Guoping Feng, emphasized how many autism-associated mutations in synaptic proteins promote pathological anxiety. She described her research that is aimed at discerning where in the brain’s neural circuitry that vulnerability might lie. In her ongoing work, Riggs is zeroing in on a novel thalamocortical circuit between the anteromedial nucleus of the thalamus and the cingulate cortex, which she found drives anxiogenic states. Riggs is co-supervised by Professor Fan Wang.

After the wide-ranging talks, supplemented by further discussion at the panels, the last word came via video conference from Kelsey Martin, executive vice president of the Simons Foundation Autism Research Initiative. Martin emphasized that fundamental research, like that done at the Simons Center, is the key to developing future therapies and other means of supporting members of the autism community.

“We believe so strongly that understanding the basic mechanisms of autism is critical to being able to develop translational and clinical approaches that are going to impact the lives of autistic individuals and their families,” she said.

From studies of synapses to circuits to behavior, MIT researchers and their collaborators are striving for exactly that impact.

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Published on The Digital Insider at https://is.gd/5E9M9z.