Monoaminergic and limbic systems underlying narcolepsy-cataplexy

Project Summary/Abstract: Regulation of sleep and arousal states is delicately balanced by a network of distinct brain regions. In patients with narcolepsy, this balance is disrupted, leading to excessive daytime sleepiness, and disrupted nighttime sleep. Patients with narcolepsy also experience cataplexy: abrupt muscle atonia during waking, often in response to strong, positive emotions. Despite significant research efforts, it remains unclear what mechanisms functionally regulate cataplexy. Muscle atonia is regulated by brainstem regions such as the ventrolateral periaqueductal gray and adjacent lateral pontine tegmentum (vlPAG-LPT), which is directly innervated by neurons in the limbic system, including the nucleus accumbens (NAc) and central nucleus of the amygdala (CeA). The NAc and CeA mediate responses to positively valenced stimuli and are densely innervated by the dopamine system, while the vlPAG-LPT is innervated by neurons in the locus coeruleus, the primary source of norepinephrine in the brain. The goal of this proposal is to clarify how monoaminergic systems and limbic-brainstem projections promote cataplexy and disrupted sleep in narcolepsy. First, we will characterize the precise temporal dynamics of dopamine release in the NAc during cataplexy and changes in state, as well as determine if stimulating dopamine release in the NAc is sufficient to drive cataplexy. Next, we will identify the release dynamics of norepinephrine in the vlPAG-LPT and determine if increasing noradrenergic tone in the brainstem is sufficient to alleviate cataplexy propensity. Finally, to elucidate the functional connectivity between the limbic system and muscle atonia-generating regions, we will record and manipulate neurons in the NAc and CeA that project to the vlPAG-LPT to evaluate if these projections regulate muscle atonia. We will use a combination of in vivo fiber photometry and fluorescence-based monoaminergic sensors, Ca2+ recording, circuit-specific opto- and chemogenetics, and chronic recording of EEG/EMG in freely moving animals to investigate these circuits. The proposed research is significant as it will meaningfully contribute to our understanding of the circuitry underlying narcolepsy symptoms, regulation of arousal states, and establish a relationship between emotional processing and muscle tone. The proposed research is also innovative as it will utilize state-of-the- art, multidisciplinary approaches to define the neural underpinnings through which monoaminergic and limbic systems act to mediate muscle atonia and disrupted sleep. Collectively, this information will significantly improve our understanding of REM sleep circuitry and narcolepsy, leading to development of more effective treatments of narcolepsy and other disorders resulting in disrupted sleep and abnormal motor control across states, such as REM-sleep behavior disorder and obstructive sleep apnea.