REM sleep control by the sublaterodorsal tegmental nucleus glutamatergic neurons

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Rapid eye movement (REM) sleep is characterized a desynchronized electroencephalogram (EEG) similar to wakefulness, low electromyogram (EMG) indicative of skeletal muscle atonia, rapid eye movements, autonomic instability, and reports of vivid dreaming. REM sleep disturbances contribute to a number of brain diseases including the sleep disorders narcolepsy/cataplexy and REM sleep behavior disorder (RBD). REM sleep is tightly controlled by a complex neural network in which the core circuits for REM sleep generation are located in the brainstem. The sublaterodorsal nucleus (SLD) of the dorsolateral pons is a critical substrate containing the core circuits. Subsets of SLD glutamatergic neurons are predominantly active during REM sleep and promote the transition to REM sleep. Yet how these REM onset neurons perform these functions remains poorly understood because we lack a deeper understanding of the molecular identities of these neurons and a complete diagram of the circuit(s) in which they are located. This is largely due to the heterogenous nature of the SLD region, which contains intermingled REM and wake-active neurons, and the limited precision and specificity afforded by traditional techniques. The central goal of this project is to molecularly define the REM onset populations within the SLD and to functionally evaluate their causal role in controlling REM sleep. Using two unbiased high-throughput sequencing approaches, we will anatomically target SLD REM neurons and identify their specific molecular markers (Aim 1). Using bidirectional optogenetic manipulation, we will then test whether candidate neurons expressing these markers can promote REM sleep (Aim 2). Molecular identification of novel REM neurons in the SLD will provide genetic access to the core circuits for REM sleep generation and thereby advance our understanding of the circuit mechanisms underlying REM sleep control. The results of this project should help open the door to the development of circuit-based therapeutic interventions for narcolepsy/cataplexy and RBD.