Journal article
Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner
The Journal of neuroscience, Vol.45(16), e1531242025
04/16/2025
DOI: 10.1523/JNEUROSCI.1531-24.2025
PMCID: PMC12005242
PMID: 39965929
Abstract
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
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.
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
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.
Details
- Title: Subtitle
- Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner
- Creators
- Genesis Omana Suarez - Florida Atlantic UniversityDivya S Kumar - Max Planck Florida Institute for NeuroscienceHannah Brunner - University of IowaAnneke Knauss - University of IowaJenifer Barrios - Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242, USAJalen Emel - University of IowaJensen Teel - Max Planck Florida Institute for NeuroscienceValentina Botero - University of IowaConnor N Broyles - University of IowaAaron Stahl - University of IowaSalil S Bidaye - Max Planck Florida Institute for NeuroscienceSeth M Tomchik - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.45(16), e1531242025
- DOI
- 10.1523/JNEUROSCI.1531-24.2025
- PMID
- 39965929
- PMCID
- PMC12005242
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- SOC NEUROSCIENCE; WASHINGTON
- Grant note
- Roy J. Carver Charitable TrustUniversity of Iowa Office of the Vice President for ResearchCarver College of MedicineCollege of Liberal Arts and SciencesNIH/NINDS: R01 NS097237, R01 NS126361, R01 NS114403, R21 NS124198 DOD CDMRP: NF230039
We thank Timothy Stelmat for designing and constructing lighted enclosures for the open-field experiments and Luis Vivas for the assistance with Python and MATLAB code. Flies obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and the Vienna Drosophila Resource Center (VDRC,www.vdrc.at) were used inthis study. Imaging was carried out at the University of Iowa Central Microscopy Research Facility (CMRF).Acquisition of the CMRF Leica SP8 Laser Scanning Confocal microscope with STED capability was made possible by a generous grant from the Roy J. Carver Charitable Trust; additional CMRF funding was provided by the University of Iowa Office of the Vice President for Research, the Carver College of Medicine, and the College of Liberal Arts and Sciences. This research was supported by NIH/NINDS R01 NS097237, R01 NS126361, R01 NS114403, R21 NS124198, and DOD CDMRP NF230039. We thank Lisa Ringen, Linda Buckner, Rob Svetly, Kathleen O'Brien, and Melissa Benilous for their administrative support.
- Language
- English
- Electronic publication date
- 02/18/2025
- Date published
- 04/16/2025
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984792366302771
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