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Table 1 Rodent narcolepsy models produced by genetic engineering

Table 1 Rodent narcolepsy models produced by genetic engineering

* T. Sakurai, Institute of Basic Medical Science, Departments of Pharmacology, University of Tsukuba, Ibaraki 305-8575, Japan; T. Sakurai and M. Yanagisawa, ERATO Yanagisawa Orphan Receptor Project, Japan Science and Technology Corporation, Tokyo 135-0064, Japan; M. Mieda, Department of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.

Collapsed Posture

Figure 1. Comparison of behavioral arrests by infrared videophotography in knockout mice. (A) Time-lapse images portraying an abrupt arrest, rarely observed in an OX2R ''' mouse. Note the collapsed posture in the second panel. (B) Time-lapse images portraying a gradual arrest in an OX2R''' mouse. "Nodding" behavior (second panel) occurs just prior to postural collapse (third panel). (Modified from ref. 5).

Figure 1. Comparison of behavioral arrests by infrared videophotography in knockout mice. (A) Time-lapse images portraying an abrupt arrest, rarely observed in an OX2R ''' mouse. Note the collapsed posture in the second panel. (B) Time-lapse images portraying a gradual arrest in an OX2R''' mouse. "Nodding" behavior (second panel) occurs just prior to postural collapse (third panel). (Modified from ref. 5).

No sign of serum electrolyte imbalance or hypoglycemia was observed in orexin mice. Bodily collapse associated with episodic rocking behavior initially suggested the possibility of a seizure disorder in the orexin-' mice. However, electroencephalograph/electromyographic (EEG/EMG) recordings from orexinmice showed no evidence of epileptic seizure. Rather, these EEG/EMG recordings revealed abnormal intrusions of REM sleep into wakefulness and fragmentation of sleep/wakefulness cycle (Figs. 2 and 3). Reduced latency to REM sleep and increase in REM sleep during the dark phase were also observed (Fig. 4). These behavioral and electrophysiological characteristics of orexin'/' mice were strikingly similar to characteristics human narcolepsy-cataplexy; Human narcolepsy-cataplexy is a debilitating neurological disease characterized by disorganization of behavioral states. This disorder affects approximately 1 in 2000 individuals in the United States.3 Most cases of human narcolepsy usually start during adolescence. A cardinal symptom of the

Narcolepsy Orexin

Figure 2. Typical EEG/EMG traces during behavioral arrests in orexin '' and OX2R '' mice. Solid and gray arrows demarcate onsets and terminations of arrests, respectively. Gray bars reflect the timing of gait disturbances and rocking behavior associated with arrests. Behavioral states are classified as awake, non-REM sleep, or REM sleep based on EEG/EMG features. (A) Abrupt arrest in orexin'' mouse. Excited ambulation (high-amplitude nuchal EMG) accompanied by an EEG typical of normal active wakefulness (low-amplitude, mixed frequency activity) gives way to rapid onset of ataxic gait, reduced neck tone, and an EEG resembling REM sleep. Postural collapse is accompanied by neck atonia and continued REM sleep EEG. Rocking behavior from limb movement occurs exclusively during periods with EEG/EMG indistinguishable from REM sleep pattern. Residual low-amplitude noise remaining in the EMG during atonia consists primarily of electrocardiographic contamination. (B) Gradual arrest in OX2R'/' mouse. Feeding behavior with high-amplitude EMG and a waking EEG gives way to gradual onset of postural collapse with reduced but not atonic nuchal EMG and transition to an EEG indistinguishable from non-REM sleep. The mouse remains immobile until sudden recovery of waking EEG and purposeful behavior. (Modified from ref. 5).

Figure 2. Typical EEG/EMG traces during behavioral arrests in orexin '' and OX2R '' mice. Solid and gray arrows demarcate onsets and terminations of arrests, respectively. Gray bars reflect the timing of gait disturbances and rocking behavior associated with arrests. Behavioral states are classified as awake, non-REM sleep, or REM sleep based on EEG/EMG features. (A) Abrupt arrest in orexin'' mouse. Excited ambulation (high-amplitude nuchal EMG) accompanied by an EEG typical of normal active wakefulness (low-amplitude, mixed frequency activity) gives way to rapid onset of ataxic gait, reduced neck tone, and an EEG resembling REM sleep. Postural collapse is accompanied by neck atonia and continued REM sleep EEG. Rocking behavior from limb movement occurs exclusively during periods with EEG/EMG indistinguishable from REM sleep pattern. Residual low-amplitude noise remaining in the EMG during atonia consists primarily of electrocardiographic contamination. (B) Gradual arrest in OX2R'/' mouse. Feeding behavior with high-amplitude EMG and a waking EEG gives way to gradual onset of postural collapse with reduced but not atonic nuchal EMG and transition to an EEG indistinguishable from non-REM sleep. The mouse remains immobile until sudden recovery of waking EEG and purposeful behavior. (Modified from ref. 5).

Wild-type

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