Early and late phases of sensory-evoked olfactory bulb inhibition are mediated by parallel local circuits: Attenuation of fast tufted cell axo-dendritic inputs to granule cells by adenosine A1 receptors

Across species, simple olfactory operations primarily utilize long-range excitatory interconnections. More complex tasks, such as fine odor discrimination and plasticity, rely on local inhibitory circuits. In the olfactory bulb, previous studies focused on measuring activity patterns following broad activation of sensory inputs and highlighted the central role canonical dendrodendritic circuits play in sculpting principal cell firing patterns. The primary goal of this study is to define the inhibitory local circuits activated by focal stimulation of a single olfactory bulb glomerulus in olfactory bulb slices prepared from rats of either sex. This approach enables dissection of circuit mechanisms normally obscured by the multi-glomerular activation patterns natural odorants elicit. Using glomerular stimulation, we identified two distinct local circuits that contribute to sensory-evoked inhibition and operate at different time periods. We further show these circuits are differentially affected by adenosine A1 receptor (A1R) activation. We utilize multiple experimental approaches to show early-phase mitral cell inhibition arises through excitatory synapses formed by axon collaterals of tufted cells onto the proximal dendrites of GABAergic granule cells. Blockade of NMDARs greatly attenuates dendrodendritic inhibition but fails to block the large initial phase of mitral cell inhibition. By contrast, activation of A1Rs attenuates both early-phase mitral cell inhibition and the underlying axo-dendritic excitation of granule cells. We conclude that two independent bulbar excitatory circuits converge on granule cells to generate temporally distinct phases of sensory-evoked inhibition, with A1R activation revealing a novel tufted cell-mediated pathway that contributes to early-phase responses. Significance statement Odor discrimination relies on precise patterns of olfactory bulb activity, but how different odors trigger distinct neural responses remains a central unsolved problem. While multiple lines of evidence demonstrate that both excitatory and inhibitory synaptic inputs are involved in shaping firing responses of olfactory bulb principal cells, how the local circuits generating these inputs function in response to sensory stimulation is only partially understood. Using intracellular recordings from brain slices, we identified two distinct inhibitory local circuits that play different roles in shaping responses to sensory input. One well-established pathway appears to contribute primarily to shaping long-duration responses while the novel, adenosine receptor-modulated pathway we describe controls the critical initial phase of odor responses.