CCKergic Tufted Cells Regulate Odor Sensitivity by Controlling Mitral Cell Output in the Mouse Olfactory Bulb.

Despite the importance of odor detection to the survival of most animals, mechanisms governing olfactory sensitivity remain unclear, especially beyond the olfactory sensory neurons (OSNs). Here we leverage opto- and chemo-genetics to selectively modulate activities of CCKergic tufted cells (TCs) in the mouse olfactory bulb (OB) of either sex, which form the intrabulbar associational system (IAS) to link isofunctional glomeruli, to determine the functional impact on OB output via mitral cells (MCs) and odor detection in behaving animals. NMDA receptors in CCKergic TCs remarkably amplify the OSN-evoked monosynaptic responses in these excitatory neurons, which provide a long-lasting feedforward excitation to MCs via both chemical transmission and electrical synapses between their apical dendrites. NMDA receptors in MCs mediate late components of the dendrodendritic TC→MC transmission to significantly boost MC outcome. Congruently, optogenetic inhibition of the CCKerigic TCs dramatically reduces the OSN-evoked MC responses. Unexpectedly, optogenetic activation of the axons projecting from CCKergic TCs on the opposite side of the same bulb produces a mainly AMPA receptor-mediated excitatory responses in MCs, leading us to speculate that CCKergic TCs functionally synchronize MC output from mirror glomeruli. Furthermore, chemogenetic inhibition of CCKergic TCs reduces animal's sensitivity to odors by elevating detection threshold, consistent with the key role of these TCs in functionally controlling MC output. Collectively, our results delineate the cellular and circuit mechanisms allowing the CCKergic TCs to regulate MC output from glomeruli on both medial and lateral side of each OB and the system's sensitivity to odors possibly via the IAS.Significance Statement The detection and processing of chemical stimuli, such as environmental odorants, are essential for the central nervous system to generate appropriate behavioral responses in animals. Most of our current knowledge about odor detection comes from studies on the interactions between chemical stimuli and odorant receptors on olfactory sensory neurons (OSNs) at the periphery. In this study, we have identified a specific subpopulation of nerve cells that play a crucial role in converting sensory input into biological signals within the olfactory bulb, the downstream target of OSNs and the initial site of synaptic odor processing. Our findings provide new insights into the cellular and circuit-level mechanisms that regulate olfactory detection beyond sensory neurons.