Around 1 in 2000 people suffer from the sleep disorder narcolepsy. The word comes from narco, meaning numbness, and lepsy, meaning seizures. It is a life-long disorder characterized by daytime sleepiness, sleep paralysis and fragmentation, vivid hallucinations during sleep transition, and cataplexy, which is the sudden loss of muscle tone while conscious often triggered by strong emotions like fear or laughter. Narcoleptic attacks usually last less than five minutes and can vary in severity. The people who suffer from this disorder experience depression, fatigue, stress, and memory loss as well as disruptions to their daily life. There have been several studies linking the wakefulness and arousal regulating neuropeptide orexin, normally produced in the hypothalamus (the primary hormonal control center of the brain) with narcolepsy. Those suffering from narcolepsy have been found to have a profound loss of orexin-producing neurons. Animals that have had the orexin gene either mutated or deleted have been used as models for further study on narcolepsy.

Cataplexy can be triggered by both positive and negative emotions. In animals, these triggers include food, wheel-running, and predator odour. Though the exact nature of cataplexy remains unclear, it is thought to be linked with the amygdala. The amygdala is part of the brain’s limbic system, the area tied to emotion, long-term memory, and motivational functions. The amygdala is important for emotional processing and reactions and is a key component in the ability to feel emotions and perceive them in others. In a study in 2013, the amygdala in mice was purposefully injured (lesioned) which reduced positive emotion-induced cataplexy. Though not a viable human treatment option, that study (among others) demonstrated a link between emotion-induced cataplexy and the amygdala. It was hypothesised that transferring orexin genes into surrogate amygdala neurons could reduce spontaneous and emotion-induced cataplexy in narcoleptic mice missing the orexin gene.

Liu et al., in the study published in February 2016, successfully blocked spontaneous and emotion-induced cataplexy and increased waking in narcoleptic mice. They used the predator odour of coyote urine as the negative emotion-inducing stimulus and it did not trigger cataplexy in the mice given the orexin gene transfer. The control groups were three times more likely to have spontaneous bouts of cataplexy than the gene transfer mice under conditions of no predator odour. Under conditions with exposure to predator odour, the control groups were five times more likely than the gene transfer mice to suffer an cataplexy attack. The gene transfer group also spent more time awake in the presence of the predator odour than the control groups, evidenced by the reduction in total non-REM sleep.

There were a certain number of criteria that had to be met to identify cataplexy in the narcoleptic mice. The mouse had to be awake and engaged in active behaviour before the attack. The attack had to last 12 seconds’ minimum and there had to be loss of muscle tone. Theta waves (4-12 Hz) had to be present and delta wave (1-4 Hz) activity had to be diminished. Such waves are recorded by an EEG and the amplitude and frequency are related to states of consciousness and brain activity. Delta waves are typically associated with deep sleep (also called slow-wave sleep). In rodents, theta waves are present during active wakefulness and REM-sleep. REM-sleep and wakefulness look quite similar in terms of brain activity, which is one of the reasons why REM is called paradoxical sleep. The brain’s cortical areas are quite active but there is no corresponding muscle tone or motor activity. Activation of the motor neurons in the spinal cord is blocked by the pons, so as to inhibit any dream motor impulses. The pons is located in brain stem right above the spinal cord and acts as a signal bridge. It also contains nuclei important for body functions. It is a crucial area in the orexin-amygdala circuit as pons regulate muscle tone. The neurons in the pons receive inhibitory signals from the amygdala and excitatory signals from the hypothalamus (via orexin neurons) on how to maintain muscle tone during emotional stress. In narcoleptic mice, the orexin excitatory signal is missing. There is nothing to balance the inhibitory signal sent to the pons from the amygdala once it’s activated by emotional activity and muscle tone is weakened. Restoration of this neural circuit by the transfer of orexin into surrogate amygdala neurons balances the inhibition and excitatory signals on muscle tone so that narcoleptic mice no longer suffer cataplexy in response to emotion-induced stimuli.

Reference:

Liu, M., Blanco-Centurion, C., Konadhode, R. R., Luan, L. and Shiromani, P. J. (2016), Orexin     gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice. Eur J Neurosci, 43: 681–688. doi:10.1111/ejn.13158