The important role of genetics in autism development has become increasingly obvious. Many genes implicated in autism are so fundamental to basic neurobiology that species as diverse as worms and humans share them. After discovering that natural variability in autism-related genes correlates with alterations in worm social behavior, Audrey Brumback, MD, PhD, pediatric neurologist and an assistant professor in the Department of Neurology, and Jon Pierce, PhD, in UT Austin’s College of Natural Sciences, hypothesized that these changes could provide a way to rapidly screen potential treatments for individuals with specific genetic causes of autism.
Leveraging C. elegans as a minimum animal model, Brumback and Pierce can screen thousands of FDA-approved drugs to quickly and inexpensively identify personalized treatment for autism based on a patient’s genetic profile. They were recently awarded a three-year, $500,000 R01 grant from the National Institute of Mental Health entitled “High-Throughput Interrogation of Autism Risk Genes: From Molecules to Behavior” to uncover the molecular mechanisms by which autism genes influence worm social behavior.
This new grant builds on another recent $1,500,000 grant from the National Institute of Mental Health for “Functional Architecture of the Mediodorsal Thalamus.” For this work, Brumback’s team will use mice to map the structure and function of a part of the thalamus that is thought to affect conditions such as autism, attention-deficit/hyperactivity disorder, and schizophrenia. The thalamus is typically considered a relay center that facilitates the transfer of incoming sensory messages to the brain cortex, using the incoming sensory information to modulate the activity of cortical neurons. As one of the largest thalamic nuclei, the mediodorsal thalamus reciprocally connects with multiple cortical and subcortical brain regions, provides a strong projection to the medial prefrontal cortex, and coordinates the activity of cortical microcircuits there during prefrontal-dependent behaviors.
Despite the importance of the mediodorsal thalamus in a range of behaviors and human disease, little is known about the physiology of the neurons in this region or how they influence behavior. In preliminary work, Brumback discovered that two populations of neurons in the mediodorsal thalamus have distinct structural and functional profiles. Based on her preliminary work and how these two thalamic circuits connect differently to the rest of the brain, she hypothesizes that each circuit is responsible for a different aspect of behavior: one circuit is responsible for social or emotional behaviors, while the other circuit modulates cognitive functions like attention and working memory.
In the funded studies, Brumback’s team will directly test this model using a neuromodulation approach called optogenetics. Using flashes of light delivered directly into the brain via a fiber optic probe, she will activate or inactivate specific populations of neurons with millisecond precision while mice perform a battery of behavioral tasks. By turning each of the proposed circuits on or off during different types of behavior, she can test which circuit is important for each type of behavior. The team will also determine how individual neurons in these two thalamic circuits integrate synaptic inputs from different brain regions. The team’s future work will decipher how these and other thalamic circuits are altered in autism and whether they can be modified to treat cognitive or social emotional symptoms.
Article Courtesy of the Neurotransmitter
