Monoaminergic signaling during mammalian NREM sleep - Recent insights and next-level questions

Subcortical neuromodulatory activity in the mammalian brain enables flexible wake behaviors, which are essential for survival in an ever-changing external environment. With the suppression of such behaviors in sleep, this activity is, on average, much reduced. Recent discoveries, enabled by unprecedented technical advancements, challenge the long-standing view that monoaminergic systems-noradrenaline (NA), dopamine (DA), and serotonin (5-HT)-remain largely inactive during sleep. This review highlights recent technological and scientific progress in this field, summarizing evidence that monoaminergic signaling in the brain supplements sleep with essential wake-related functions. Stress and/or neuropsychiatric conditions negatively impact on monoaminergic signaling, which can lead to sleep disruptions. Furthermore, subcortical neuromodulatory systems are vulnerable to neurodegenerative pathologies, which implies them in sleep disruptions at early stages of disease. We propose that future research will be well-invested in elucidating the spatiotemporal organization, cellular mechanisms, and functional relevance of neuromodulatory dynamics across species, and in identifying the molecular and physiological processes that sustain their integrity throughout the lifespan.