Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Trace amine-associated receptor 1 (TAAR1) agonists exhibit diverse physiological effects, including wake promotion.
• The specific role of TAAR1 in regulating sleep-wake cycles and cortical activity remains largely unexplored.

Purpose of the Study:

• To investigate the function of TAAR1 in regulating sleep/wake states and cortical activity using genetically modified mice and pharmacological agents.
• To determine the effects of TAAR1 modulation on electroencephalography (EEG), electromyography (EMG), body temperature, and locomotor activity.

Main Methods:

• Recorded EEG, EMG, body temperature, and locomotor activity in Taar1 knockout (KO), overexpressing (OE), and wild-type (WT) mice under baseline and sleep-deprived conditions.
• Administered TAAR1 partial agonist RO5263397 and caffeine to assess their effects on sleep/wake parameters and cortical activity across different Taar1 genotypes.
• Analyzed spectral power, particularly theta and gamma frequencies, during NREM and REM sleep and wakefulness.

Main Results:

• TAAR1 overexpression modestly increased baseline wakefulness.
• TAAR1 partial agonism with RO5263397 increased wakefulness, reduced NREM and REM sleep, decreased gamma power, and lowered body temperature in WT mice, with effects absent in KO and potentiated in OE mice.
• Caffeine's wake-promoting effects were modulated by Taar1 genotype, being attenuated in KO and potentiated in OE mice.

Conclusions:

• TAAR1 plays a modulatory role in regulating sleep/wake states and cortical activity.
• TAAR1 partial agonism promotes wakefulness and reduces sleep, highlighting TAAR1 as a potential therapeutic target for wake-promoting interventions.