Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.

By J. Hara, C. Beuckmann, Tadahiro Nambu, J. Willie, R. Chemelli, C. Sinton, F. Sugiyama, K. Yagami, K. Goto, M. Yanagisawa and 1 more. Neuron, 2001

1,435 citations recorded by the source corpus.

Orexins (hypocretins) are a pair of neuropeptides implicated in energy homeostasis and arousal. Recent reports suggest that loss of orexin-containing neurons occurs in human patients with narcolepsy. We generated transgenic mice in which orexin-containing neurons are ablated by orexinergic-specific expression of a truncated Machado-Joseph disease gene product (ataxin-3) with an expanded polyglutamine stretch. These mice showed a phenotype strikingly similar to human narcolepsy, including behavioral arrests, premature entry into rapid eye movement (REM) sleep, poorly consolidated sleep patterns, and a late-onset obesity, despite eating less than nontransgenic littermates. These results provide evidence that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis. Orexin/ataxin-3 mice provide a valuable model for studying the pathophysiology and treatment of narcolepsy.

Subfields: Cognitive Neuroscience, Endocrine and Autonomic Systems, Experimental and Cognitive Psychology

View Paper: https://www.semanticscholar.org/paper/a0045e3349d0b617ab66fe2e0f9cec0dcd0c6663

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In Cognitive Neuroscience

1. T. Sakurai
2. J. Siegel
3. J. Elmquist

In Endocrine and Autonomic Systems

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In Experimental and Cognitive Psychology

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Citations in the corpus

• Behavioral correlates of activity in identified hypocretin/orexin neurons. (2005, positive): “In rodents, cataplexy is most frequently linked to exploration, burrowing, and investigation of the environment (Chemelli et al., 1999; Hara et al., 2001).”
• Hypothalamic orexin neurons regulate arousal according to energy balance in mice. (2003, positive): “Additionally, we per-and orexin/ataxin-3 transgenic mice are indicated by formed whole-cell patch-clamp studies with hypothala-hypophagia, obesity, and inactivity relative to control mic slice preparations from orexin/EGFP transgenic littermates (Willie et al., 2001; Hara et al., 2001).”
• The Human Obesity Gene Map: The 2005 Update (2006, background): “Expression of Mjd (Ataxin 3) with expanded repeats in orexinergic neurons Late-onset obesity (C57BL/6J and DBA/2 mixed genetic background) (417)”
• The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. (2002, result): “These subjects also had moderately increased BMI (Table 2), as previously reported in humans(2,3,38,39) and mice with hypocretin cell loss.(51) Some patients had recent onset of narcolepsy (eg, 6 months), indicating that hypocretin deficiency is already established at presentation.”
• Discharge of Identified Orexin/Hypocretin Neurons across the Sleep-Waking Cycle (2005, background): “…the capacity to stimulate metabolism in parallel with activity through influences on the sympathetic nervous system, the hypothalamo–pituitary–adrenal axis and hypothalamo– pituitary–thyroid axis (Ida et al., 2000; Hara et al., 2001; Espana et al., 2003; Monda et al., 2003; Yamanaka et al., 2003).”
• Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. (2003, background): “Northern blots of whole-brain RNA neurons have essentially identical behavioral abnormali- revealed attenuation of OX2R mRNA expression in ties (Hara et al., 2001).”