Project D: Hypocretin and Histamine studies in the Zebrafish Hypocretin and histamine are now known to be important arousal signals. Anatomical correlates c hypocretin, histamine, and other cell groups relevant to sleep regulation, as well as the cognate homologou genes, have been identified in zebrafish and appear to anatomically interconnect similarly as in mammals We have identified a sleep-like state in zebrafish and can objectively characterize alterations in this behavio with an automated digital video system. The goal of this revised proposal is to take advantage of th attributes of the zebrafish as a genetic model organism, to develop a better understanding of factors relevan to sleep regulation in humans. Specifically, we will validate the zebrafish as a model for the study of sleep disturbances in relationship to hypocretin and histamine through the use of transgenic and gene-targeted zebrafish by characterization of the behavioral effects of loss of, or overexpression of hypocretin (HCRT) o histidine decarboxylase (HOC) and loss of expression of their relevant receptors (hypocretin recepto (HCRTR), histamine H1 receptor (H1). We hypothesize that animals deficient in hypocretinergic o listaminergic transmission will have altered rest/activity patterns. These hypothesized altered rest/activity patterns will demonstrate functional conservation of these systems in the zebrafish, and validate the use o zebrafish as a model in the study of study of sleep disturbances in relationship to hypocretin and histamine, We will also exploit the forward genetics advantages of the zebrafish to identify novel developmental genes affecting the hypocretin and histamine systems by screening for ENU-induced mutations resulting in loss of expression of HCRT, HOC and their receptors, or abnormal placement of these cells. Such novel genes may be relevant to the development of narcolepsy and hypersomnia in humans. We will also characterize these dentified mutants in terms of cellular specificity, and gene expression profiles, and behavior as a preliminary step toward positional cloning. Finally, we will genetically map the most interesting mutations (those with cell specificity and/or robust behavioral phenotype). These studies will be valuable in our understanding of the etiology of narcolepsy and hypersomnia.
| Bonvalet, Melodie; Ollila, Hanna M; Ambati, Aditya et al. (2017) Autoimmunity in narcolepsy. Curr Opin Pulm Med 23:522-529 |
| Plante, David T; Finn, Laurel A; Hagen, Erika W et al. (2016) Subjective and Objective Measures of Hypersomnolence Demonstrate Divergent Associations with Depression among Participants in the Wisconsin Sleep Cohort Study. J Clin Sleep Med 12:571-8 |
| Gottlieb, D J; Hek, K; Chen, T-H et al. (2015) Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. Mol Psychiatry 20:1232-9 |
| Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang et al. (2015) HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet 96:136-46 |
| Li, Jason; Moore 4th, Hyatt; Lin, Ling et al. (2015) Association of low ferritin with PLM in the Wisconsin Sleep Cohort. Sleep Med 16:1413-1418 |
| Kornum, Birgitte Rahbek; Pizza, Fabio; Knudsen, Stine et al. (2015) Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun 49:54-8 |
| Kawai, Makoto; O'Hara, Ruth; Einen, Mali et al. (2015) Narcolepsy in African Americans. Sleep 38:1673-81 |
| Holm, Anja; Lin, Ling; Faraco, Juliette et al. (2015) EIF3G is associated with narcolepsy across ethnicities. Eur J Hum Genet 23:1573-80 |
| Jacob, Louis; Leib, Ryan; Ollila, Hanna M et al. (2015) Comparison of Pandemrix and Arepanrix, two pH1N1 AS03-adjuvanted vaccines differentially associated with narcolepsy development. Brain Behav Immun 47:44-57 |
| de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78 |
Showing the most recent 10 out of 55 publications
