Zebra Fish as a Model to Identify Genetic and Neuronal Mechanisms Through Which NF1 Regulates Sleep
Abstract
Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutation of the neurofibromin 1 (nf1) gene that results in pigmented skin patches, specific types of cancers, and a variety of behavioral problems that include disrupted sleep. NF1 is commonly associated with trouble both falling asleep and staying asleep at night, which typically results in drowsiness during the day. This disrupted sleep directly affects quality of life and likely also exacerbates some of the other behavioral and physiological symptoms associated with NF1. Human and animal studies suggest that this disrupted sleep is a direct effect of mutation of the nf1 gene rather than a secondary consequence of other symptoms caused by mutation of nf1. However, it is not known why mutation of nf1 results in disrupted sleep. Answering this question is the first step that is necessary in order to identify new therapies to treat the disrupted sleep that occurs in individuals with the NF1 disorder, which may also help to reduce some of the other behavioral and physiological symptoms associated with NF1. Due to the challenges involved in performing controlled experiments using humans, identifying the mechanisms through which mutation of nf1 results in disrupted sleep will require experiments that use animals whose nf1 gene is mutated and exhibit symptoms that are similar to those observed in humans with the NF1 syndrome. A promising animal model for these studies is the zebrafish, a relatively simple vertebrate animal that has recently emerged as a useful model to discover and characterize mechanisms that regulate sleep. Indeed, work from several laboratories has generated extensive evidence that sleep mechanisms that have been identified in humans and rodents are broadly conserved in zebrafish. Zebrafish are particularly useful for sleep studies because many animals can be tested in parallel, which allows the effects of many different genes and drugs on sleep to be tested more efficiently and inexpensively than is possible using humans or rodents. Zebrafish are also transparent, which together with their relatively small brain, makes it possible to monitor the activity of essentially every neuron in the brain when the animals are awake and asleep, enabling efficient discovery of neurons that underlie disrupted sleep. An advantage of using zebrafish for this project is that they exhibit sleep after only 5 days of development before the emergence of more complex behaviors or cancers that can complicate interpretation of human and rodent NF1 sleep studies. Zebrafish containing a mutation in the zebrafish version of the human nf1 gene have been generated and shown to reproduce many features of the human NF1 disorder; in preliminary studies, we found that these nf1 mutant zebrafish have sleep phenotypes that are similar to those observed in humans with NF1. We propose to use this zebrafish model to identify the genes and neurons that underlie the disrupted sleep that is observed in nf1 mutant animals. Once we identify these genes and neurons in zebrafish, they can be confirmed by experiments that use rodents and, ultimately, humans. Discoveries made by this project will likely suggest novel therapies to treat the disrupted sleep that commonly occurs in the human NF1 disorder. Since disrupted sleep often exacerbates the behavioral and physiological symptoms associated with disease, these therapies may also improve some of the other behavioral and physiological symptoms observed in the human NF1 disorder. Previous studies have shown that similar mechanisms regulate sleep in zebrafish and mammals, suggesting that most findings from our zebrafish study will be applicable to humans. It is difficult to predict how long it will take this basic research project to result in a new therapy for NF1. However, we estimate that human tests of new therapies could potentially begin within 5 years if we identify a mechanism for which FDA-approved drugs a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210179
Entities
People
- David Prober
Organizations
- California Institute of Technology
- United States Army