Feeding-elicited cataplexy in orexin knockout mice

Abstract

Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad lib regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 hr after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the foodanticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…Modeling of orexin neuron activity suggests that dynorphin is capable of modulating orexin responses, delaying its arousal effects at the sleep/wake transition by affecting the sensitization and firing rate of orexinsensitive neurons (Williams and Behn, 2011). Nevertheless, orexin peptide knockout animals have provided a useful model in which to study the cataplectic episodes in detail, where both scheduled palatable food and running wheel presentation effectively increase the frequency of cataplectic episodes, presumably mimicking the effect of positive emotions in human patients (Españ a et al, 2007;Clark et al, 2009). Consistent with this observation is the finding that both positive and negative olfactory stimuli (female and coyote urine) are also sufficient to induce narcoleptic episodes in male orexin peptide knockout mice (Morawska et al, 2011).…”

Challenges in the development of therapeutics for narcolepsy

“…Interventions that significantly increase cataplexy frequency have included stimuli intended to evoke strong emotions, such as novel environments (Mieda et al, 2004), controlled access to running wheels (Espana et al, 2007), highly palatable food (Clark et al, 2009) including chocolate (Oishi et al, 2013; Tabuchi et al, 2014), the combination of chocolate and running wheels (Burgess et al, 2013), and attractive or aversive odors (Morawska et al, 2011). While chocolate has been shown to be highly effective at increasing cataplexy from 1.6-fold (Tabuchi et al, 2014) to 8.1-fold (Oishi et al, 2013), it could potentially confound studies by introducing dietary changes or secondary effects of prolonged wakefulness.…”

Food for Thought: Understanding the Multifaceted Nature of Orexins

“…Studies have shown that central orexin injections induce feeding in rats and mice (1,2). Conversely, central administration of orexin receptor-1-selective antagonist greatly reduced food intake in rats (31), whereas orexinknockout and orexin neuronal-ablated mice exhibit reduced feeding behavior (32)(33)(34)(35). Other studies suggest that orexin neurons are sensitive to energy status cues, such as glucose levels (31).…”