Orexins (hypocretins) are peptide neurotransmitters produced by a small group of neurons located exclusively in the lateral hypothalamus (LH). Orexins modulate arousal, and as a result, have profound effects on feeding behavior and the sleep-wake cycle. Loss of orexin producing neurons leads to a narcoleptic phenotype, characterized by sudden transitions from vigilance to rapid eye movement (REM) sleep (direct transition to REM, DREM) observed in electroencephalogram (EEG) and electromyogram (EMG) recordings. In this study, we demonstrate that mice lacking the basic helix-loop-helix transcription factor O/E3 (also known as ebf2) have a decrease in orexin-producing cells in the LH, in addition to a severely impaired orexinergic innervation of the pons. These changes in the orexinergic circuit of O/E3-null animals induce a narcoleptic phenotype, similar to the one arising in orexin-deficient and orexin-ataxin-3 mice. Taken together, our results suggest that O/E3 plays a central role during the establishment of a functional orexinergic circuit by controlling the expression of essential hypothalamic neurotransmitter and the correct development of the nerve fibers arising from the hypothalamus. This is the first report regarding the narcolepsy-cataplexy syndrome in O/E3-null mice, which adds the importance of transcription factors in the regulation of neural subpopulations that control the sleep-wake cycle.
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|Published - 2 Jun 2011
Bibliographical noteFunding Information:
This work was supported by CONACyT grant 56295 to R. Vidaltamayo and UNAM-DGAPA-PAPIIT grants IN208311 to R. Vidaltamayo and IN225209 to R. Drucker-Colín. We would like to thank Dr. Óscar Prospero-García for his assistance with the EEG/EMG recordings, Dr. Raúl Aguilar-Roblero for his guidance in the statistical analysis, Gabriel Orozco-Hoyuela for his support with the confocal microscopy image acquisition and Teresa Torres-Peralta, María Valverde, Francisco Pérez-Eugenio and Eduardo Blanco-Hernández for their technical assistance. Mitra Cowan, now at McGill University, kindly provided the 129S2/SvPasCrl ES cell line used to generate the O/E3-LNL allele. R. Vidaltamayo generated the O/E3-null mice while working under contract to Howard Hughes Medical Institute at Randall R. Reed's laboratory at Johns Hopkins University School of Medicine, who kindly provided the homology arms used to target the insertion of the null allele at the O/E3 locus and the founder animals to expand the colony at IFC, UNAM. We would also like to thank the Doctorado en Ciencias Biomédicas of the Universidad Nacional Autónoma de México and the DGIP of the Universidad Autónoma de Sinaloa for their support.
Copyright 2011 Elsevier B.V., All rights reserved.
All Science Journal Classification (ASJC) codes
- General Neuroscience