Abstract
Acute chemogenetic inhibition of histamine (HA) neurons in adult mice induced nonrapid eye movement (NREM) sleep with an increased delta power. By contrast, selective genetic lesioning of HA neurons with caspase in adult mice exhibited a normal sleep–wake cycle overall, except at the diurnal start of the lights-off period, when they remained sleepier. The amount of time spent in NREM sleep and in the wake state in mice with lesioned HA neurons was unchanged over 24 hr, but the sleep–wake cycle was more fragmented. Both the delayed increase in wakefulness at the start of the night and the sleep–wake fragmentation are similar phenotypes to histidine decarboxylase knockout mice, which cannot synthesize HA. Chronic loss of HA neurons did not affect sleep homeostasis after sleep deprivation. However, the chronic loss of HA neurons or chemogenetic inhibition of HA neurons did notably reduce the ability of the wake-promoting compound modafinil to sustain wakefulness. Thus, part of modafinil’s wake-promoting actions arise through the HA system.
Highlights
The neuromodulator histamine (HA), whose neurons are located in the tuberomammillary nucleus (TMN) of the posterior hypothalamus, promotes wakefulness [1,2,3,4,5,6]
This statement is supported by extensive evidence: HA neurons are selectively wake-active [7, 8]; HA levels positively correlate with wakefulness [9]; H1 receptor inverse agonists promote nonrapid eye movement (NREM) sleep [10,11,12]; GABAA-receptorpositive allosteric modulators, such as the sleeping medication zolpidem, increase inhibition onto HA neurons and reduce the latency to NREM sleep [13]; optogenetic activation of GABAergic axons from the preoptic area in the TMN induces NREM sleep [14]; and acute optogenetic silencing of HA neurons induces NREM sleep [15]
We further examined whether the wake-promoting effect of modafinil depends on the HA system
Summary
Different ways of manipulating histamine neurons in mice, short term with chemogenetics and long term with selective lesioning, give different effects. Short-term inhibition of histamine neurons produces nonrapid eye movement sleep. The long-term effects of killing them, on the other hand, produces a milder phenotype, with increased sleep–wake fragmentation. Both approaches underline the importance of the histamine system for generating arousal. The mice with lesions or acute inhibition of histamine neurons allowed us to test the site of action of modafinil, a popular drug to boost wakefulness and cognition. The places where modafinil operates in the brain have proven difficult to localize. We show that modafinil requires histamine neurons for part of its wake-promoting effect
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