Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from mutations in the neurofibromin gene that can reduce levels of the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increased spontaneous grooming in male and female flies. This followed a nonlinear spatial pattern, with Nf1 deficiency increasing grooming of certain body parts differentially, including the abdomen, head, and wings. The increase in grooming could be overridden by hunger in foraging animals, demonstrating that the Nf1 effect is plastic and internal state dependent. Stimulus-evoked grooming patterns were altered as well, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. These results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting low-level motor functions. Significance statement Neurofibromatosis type 1 (NF1) is associated with an increased risk of cognitive and behavioral disorders, yet the underlying neuronal mechanisms remain poorly understood. Our study utilizes a Drosophila model to demonstrate that loss of neurofibromin (Nf1) expression impacts motor behavior and the prioritization of repetitive actions, such as grooming, in a hunger state-dependent manner. Our experiments also suggest that alterations in neuronal circuit activity due to the loss of Nf1 influence behavior without impairing motor coordination. Understanding how Nf1 loss affects motor function can reveal the broader neuronal mechanisms contributing to cognitive impairment, providing valuable insights for developing therapeutic strategies.