August 9, 2024
Genetic disorders such as neurofibromatosis type 1 (NF1) drive a range of symptoms, including increasing risk for cognitive and behavioral disorders such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). NF1 affects brain function, potentially by influencing neurons. A new study, currently published as a preprint, describes how the genetic mutation(s) underlying NF1 affect neuronal function, examining motor behaviors in an animal model.
Neurofibromatosis type 1 is among the most common monogenetic disorders affecting brain function. It affects cognition and behavior in several ways, with some patients experiencing impaired learning & memory, along with increased rates of ASD (over 25%) and ADHD (approximately 50%). The disease is caused by loss-of-function mutations in the NF1 gene, which normally makes a cellular protein called neurofibromin. The genetic mutations result in less functional neurofibromin protein. Given that NF1 affects the brain, loss of the neurofibromin protein must affect the brain, including the neurons that do most of the brain computations.
How does loss of neurofibromin affect neurons?
To test how loss of neurofibromin affects neurons, we have been investigating its role in the brain of the fruit fly, Drosophila. The fly is an outstanding model organism for dissecting how genes affect neurons and behavior. In earlier studies (King et al., 2016; King et al., 2020), we found that loss of neurofibromin in flies drives a surprisingly large behavioral change. The flies spontaneously groom (clean themselves) ... a lot. Up to seven times more than animals with normal levels of neurofibromin. This provided a platform to dissect the mechanisms of how neurofibromin influences neurons and behavior.
There are several major advantages to looking at a behavior like grooming. Increased grooming is reminiscent of restricted and repetitive behaviors that are engaged in certain human disorders, such as ASD. Second, the behavior reflects activity of underlying neurons - at some level in the brain, there must be an increase in neuronal activity to drive this increased grooming. Third, the circuits mediating grooming of different body parts have been carefully mapped by others. Finally, when flies get dirty (like if they get covered in dust), grooming follows a general sequence - starting with the head and moving down. This is similar to other animals, including mammals. To envision how this works, just imagine that someone threw a bucketful of dust onto you, completely coating you. The first thing you'd probably do is rub your eyes, then clean off your head, and work down from there. Cool, but how are these things helpful for understanding a genetic disorder that affects behavior? Because they allow us to examine how the function of brain circuits and behavior change when something goes wrong, such as when there isn't enough neurofibromin in neurons.
So how does reduction of neurofibromin affect neuronal circuits and behavior. To begin answering this question, we asked how loss of neurofibromin affects grooming behaviors. Does it affect grooming of all body parts equally? Does it primary affect the highest-level grooming behaviors (head grooming)? Can reducing neurofibromin selectively in specific grooming "command neurons" affect the behavior? How flexible is it - can it be overridden by other behavioral drives, such as hunger/feeding? Finally, how is the motor aspect affected - does loss of neurofibromin affect motor coordination?
Answering these questions was a major goal of this study, and the results can be found in the preprint. Genesis Omana Suarez took the lead on this project, which came out of her research in the lab spanning her undergraduate honors thesis at the FAU Wilkes Honors College, a research internship at Scripps Florida, and a postbacc at the University of Iowa. She collaborated with several members of the Tomchik lab (Hannah Brunner, Jalen Emel, Anneke Knauss, Valentina Botero, Connor Broyles, and Aaron Stahl) as well as Divya Kumar and Jensen Teel in the lab of Salil Bidaye.
For more information, see the preprint at bioRxiv.
We look forward to feedback from the scientific community on this project, and hope to have the finalized version out soon.
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