Muscle paralysis is a normal aspect of REM sleep, but dysfunction in the paralysis system gives rise to cataplexy, sudden episodes of paralysis in people with narcolepsy. Just the opposite occurs in REM sleep behavior disorder (RBD) in which people act out their dreams, often resulting in injury. With both cataplexy and RBD, the events are frequently brought on by strong emotions: cataplexy is often triggered when laughing at a joke with friends, and people with RBD often lash out when dreaming about fighting a foe. To develop better therapies for these disorders, it is essential to understand how the brain circuitry that underlies emotions regulates muscle tone. Cataplexy is mainly triggered by strong positive emotions, usually when socially interacting with close friends and family. The amygdala mediates behavioral responses to emotions, and prior research plus our pilot data suggest that cataplexy is triggered by neurons in the central nucleus of the amygdala that express the oxytocin receptor (CeAOTR). Specifically, with positive emotions, CeAOTR neurons may promote cataplexy by activating brainstem pathways that regulate the paralysis of REM sleep. Our long-term objectives are to determine the role of the CeAOTR neurons in regulating cataplexy, to define the brainstem mechanisms through which they trigger paralysis, and to identify the upstream signals through which they are activated. First, we will determine whether the CeAOTR neurons promote cataplexy by activating and inhibiting these neurons using chemogenetics. We will then record the activity of these neurons across cataplexy and sleep states using calcium imaging in freely moving mice. Next, we will define the neural targets through which the CeAOTR neurons promote cataplexy by mapping their connections to brainstem circuits that regulate muscle tone. We will establish if these neural pathways activate or inhibit these brainstem regions using brain slice recordings, and we will test the necessity of these projections using optogenetic activation or inhibition. Last, we will define the neural inputs to the CeAOTR neurons that promote cataplexy using conditional and conventional pathway tracing, and we will test if rewarding social interaction triggers cataplexy and whether this is mediated by oxytocin. Collectively, these multidisciplinary experiments will define the neural mechanisms through which positive emotions including social signals activate amygdala neurons and brainstem paralysis mechanisms. An improved understanding of how emotions regulate muscle tone should shed light on the normal regulation of muscle paralysis during REM sleep, and ultimately lead to better treatments for narcolepsy, RBD, and other disorders of muscle tone.
Emotions have a major influence on muscle tone, and cataplexy, muscle paralysis triggered by strong positive emotions and social stimuli, is a prominent problem in people with narcolepsy. These studies will shed light on the brain mechanisms through which emotions trigger paralysis in narcolepsy. More broadly, these findings will provide a better understanding of what normally regulates muscle tone during sleep and why this paralysis fails in REM sleep behavior disorder.
|Naganuma, Fumito; Bandaru, Sathyajit S; Absi, Gianna et al. (2018) Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy. Neurobiol Dis 120:12-20|