Theodore L. Baker

Canine model of narcolepsy: Genetic and developmental determinants

Abstract Genetic and developmental factors were investigated in 101 cases of canine narcoleps-cataplexy syndrome. An experimental breeding program documented a probable autosomal recessive mode of inheritance in two dog breeds, Doberman pinschers and Labrador retrievers, and in crosses between those breeds. Age of onset of cataplexy and severity of symptoms were remarkably similar in 73 subjects with the genetically transmitted form of narcolepsy. Efforts to demonstrate genetic factors by breeding affected poodles and beagles were unsuccessful. Furthermore, a positive family history could not be documented in these animals or in narcoleptic dogs of 13 other breeds. Both age of onset and severity of symptoms were highly variable within this population. We suggest there may be multiple etiologies in canine narcolepsy syndrome: (i) inheritance via a single autosomal recessive gene, which appears to be identical in at least two unrelated dog breeds; (ii) nongenetic mechanisms which may include developmental or traumatic accidents. Preliminary findings of parallel neurochemical studies in narcoleptic dogs indicate distinct abnormalities in central neurotransmitter concentration and turnover. We theorize that these neurochemical abnormalities may result from inherited disorders of synthesis and/or metabolism which are present from birth or from nongenetic neurochemical abnormalities appearing later in life. The observation that symptom characteristics are identical in all affected dogs suggests that a common neurochemical disorder may underlie both genetic and nongenetic variations of the disease.

Narcolepsy: Cholinergic receptor changes in an animal model

An inbred colony of narcoleptic doberman pinschers has been analyzed for muscarinic receptor levels in 19 discrete brain regions. In comparison to age-matched controls, receptors were generally elevated in the brainstem and reduced in forebrain areas. No changes in receptor binding affinity were detected. The increased receptor levels found in the brainstem suggest that cholinoceptive neurons in this region are hypersensitive and may be involved in the initiation of cataplexy and other aspects of the narcolepsy syndrome.

Electroencephalographic correlates of cataplectic attacks in narcoleptic canines

Cataplectic attacks were monitored behaviorally and polygraphically in 4 narcoleptic dogs, of which three inherited the disorder. The recorded EEG signals were evaluated by power spectral analysis. We found 3 distinct stages of cataplexy: an initial stage which resembled wakefulness with tonic suppression of EMG activity, a later stage which was highly similar to REM sleep, and a final transitional stage to wakefulness or NREM sleep. The first stage of cataplexy was characterized by full postural collapse, a waking-like EEG spectrum, visual tracking, and a hypotonic EMG. The second stage of cataplexy differed electrographically from the previous stage by the onset of hypersynchronous hippocampal theta activity, a REM-like EEG spectrum, larger amplitude EEG signals, and a higher peak theta frequency. Glazed eyes, sporadic rapid eye movements and muscle twitches were also present. The final stage of cataplexy was characterized by mixed amplitude, mixed frequency EEG activity, and by the absence of rapid eye movements, visual tracking, directed movements, and muscle twitches. The EEG spectra of two other narcoleptic phenomena, sleep-onset REM periods and NREM sleep onsets from cataplexy, were nearly identical to the spectra of the normally occurring REM and NREM sleep periods.

Sleep-wakefulness patterns in the aged cat

This investigation compared the 24 h sleep-wake characteristics of young adult (2-4 years) and old (10-11 years) cats in order to determine whether there were significant age- and/or gender-related differences. Aged animals had more brief (6-14 sec) awakenings, less REM sleep, and more NREM sleep than young adults. There were no significant age- or gender-related differences with respect to either the daily numbers or the mean durations of sleep and waking episodes. Compared with the young adults, aged males had substantially less DSWS and fewer numbers of short-duration (less than or equal to 2.5 min) LSWS bouts. Both males and females showed age-related differences with respect to the sequencing of state-patterns. The expression of these patterns in relation to time of day was comparable for young and old animals. Overall, these findings compare favorably with those commonly reported in the elderly human.

Sleep-related apneic and apneustic breathing following pneumotaxic lesion and vagotomy

Sleep-wakefulness state was found to be a crucial determinant of respiratory pattern in chronic cats with bilateral lesions of the rostral pontine pneumotaxic complex (PC). Lesions resulted in increased TE, TI, and VT in all sleep and waking states. Several state-specific respiratory effects were also observed: (1) comparatively eupneic breathing during alert wakefulness (WI); (2) greatly increased TE in slow wave sleep (SWS); (3) decreased TE during rapid eye movement sleep (REM), relative to SWS; (4) increased tendency for prolonged TI (brief apneusis) during REM. Bilateral vagotomy at 2-5 weeks after PC lesion exaggerated these effects and caused distinct apneusis during REM. The results confirm that the PC is not essential for the occurrence of either rhythmic breathing or for expression of state changes in respiration, although the effects of the PC on breathing in the intact cat may vary as a function of sleep-wakefulness state. It is suggested that other regulatory systems that influence the central respiratory rhythm generator (RRG) are similarly modulated by state, and that variations in respiratory pattern observed following PC lesion and vagotomy are the result of state-dependent changes in the balance between multiple inputs to the RRG.

Rapid eye movement sleep and its relationship to feeding behavior in the adult cat.

The aim of this study was to corroborate a previous report that, in cats kept on a 12:12-hr light-dark schedule, there is a highly significant negative correlation between the quantity of REM sleep in a 12-hr period and food intake in the subsequent 12-hr interval. Analyses of sleep-wake and food intake measures from freely behaving adult cats failed to disclose any consistent correlations between food consumption and REM sleep quantities in the same or adjacent 12-hr periods; amounts of waking (or total sleep) and slow-wave sleep also showed no consistent relationship to food intake. These findings question assertions that REM sleep participates directly in regulating the expression of motivated behaviors.