Adenosine A_2A receptor neurons in the olfactory bulb mediate odor-guided behaviors in mice

Depression, rapid eye movement (REM) sleep behavior disorder, and altered olfaction are often present in Parkinson's disease. Our previous studies demonstrated the role of the olfactory bulb (OB) in causing REM sleep disturbances in depression. Furthermore, adenosine A_2A receptors (A_2AR) which are richly expressed in the OB, play an important role in the regulation of REM sleep. Caffeine, an adenosine A₁ receptors and A_2AR antagonist, and other A_2AR antagonists were reported to improve olfactory function and restore age-related olfactory deficits. Therefore, we hypothesized that the A_2AR neurons in the OB may regulate olfaction or odor-guided behaviors in mice. In the present study, we employed chemogenetics to specifically activate or inhibit neuronal activity. Then, buried food test and olfactory habituation/dishabituation test were performed to measure the changes in the mice's olfactory ability. We demonstrated that activation of OB neurons or OB A_2AR neurons shortened the latency of buried food test and enhanced olfactory habituation to the same odors and dishabituation to different odors; inhibition of these neurons showed the opposite effects. Photostimulation of ChR2-expressing OB A_2AR neuron terminals evoked inward current in the olfactory tubercle (OT) and the piriform cortex (Pir), which was blocked by glutamate receptor antagonists 2-amino-5-phosphonopentanoic acid and 6-cyano-7nitroquinoxaline-2,3-dione. Collectively, these results suggest that the OB mediates olfaction via A_2AR neurons in mice. Moreover, the excitatory glutamatergic release from OB neurons to the OT and the Pir were found responsible for the olfaction-mediated effects of OB A_2AR neurons.