Olfactory stimuli have been known for a long time to elicit oscillations in olfactory brain areas. In the olfactory bulb (OB), odors trigger synchronous oscillatory activity that is believed to arise from the coherent and rhythmic discharges of large numbers of neurons. These oscillations are known to take part in encoding of sensory information before their transfer to higher subcortical and cortical areas. To characterize the cellular mechanisms underlying ␥ (30 -80 Hz) local field potential (LFP) oscillations, we simultaneously recorded multiunit discharges, intracellular responses, and LFP in rat OB slices. We showed that a single and brief electrical stimulation of olfactory nerve elicited LFP oscillations in the mitral cell body layer lasting Ͼ1 sec. Both action potentials and subthreshold oscillations of mitral/tufted cells, the bulbar output neurons, were precisely synchronized with LFP oscillations. This synchronization arises from the interaction between output neurons and granule cells, the main population of local circuit inhibitory interneurons, through dendrodendritic synapses. Interestingly enough, the synchronization exerted by reciprocal synaptic interactions did not require action potentials initiated in granule cell somata. Finally, local application of a GABA A receptor antagonist at the mitral cell and external plexiform layers confirmed the exclusive role of the granule cell reciprocal synapses in generating the evoked oscillations. We concluded that interneurons located in the granule cell layer generate synaptic activity capable of synchronizing activity of output neurons by interacting with both their subthreshold and spiking activity.

Neuronal pattern separation is thought to enable the brain to disambiguate sensory stimuli with overlapping features thereby extracting valuable information. In the olfactory system, it remains unknown whether pattern separation acts as a driving force for sensory discrimination and the learning thereof. Here we show that overlapping odor-evoked input patterns to the mouse olfactory bulb (OB) are dynamically reformatted in the network at the timescale of a single breath, giving rise to separated patterns of activity in ensemble of output neurons (mitral/tufted cells; M/T). Strikingly, the extent of pattern separation in M/T assemblies predicts behavioral discrimination performance during the learning phase. Furthermore, exciting or inhibiting GABAergic OB interneurons, using optogenetics or pharmacogenetics, altered pattern separation and thereby odor discrimination learning in a bidirectional way. In conclusion, we propose that the OB network can act as a pattern separator facilitating olfactory stimuli distinction, a process that is sculpted by synaptic inhibition.

The study of the neural basis of olfaction is important both for understanding the sense of smell and for understanding the mechanisms of neural computation. In the olfactory bulb (OB), the spatial patterning of both sensory inputs and synaptic interactions is crucial for processing odor information, although this patterning alone is not sufficient. Recent studies have suggested that representations of odor may already be distributed and dynamic in the first olfactory relay. The growing evidence demonstrating a functional role for the temporal structure of bulbar neuronal activity supports this assumption. However, the detailed mechanisms underlying this temporal structure have never been thoroughly studied. Our study focused on gamma (40-100 Hz) network oscillations in the mammalian OB, which is a form of temporal patterning in bulbar activity elicited by olfactory stimuli. We used computational modeling combined with electrophysiological recordings to investigate the basic synaptic organization necessary and sufficient to generate sustained gamma rhythms. We found that features of gamma oscillations obtained in vitro were identical to those of a model based on lateral inhibition as the coupling modality (i.e., low irregular firing rate and high oscillation stability). In contrast, they differed substantially from those of a model based on lateral excitatory coupling (i.e., high regular firing rate and instable oscillations). Therefore we could precisely tune the oscillation frequency by changing the kinetics of inhibitory events supporting the lateral inhibition. Moreover, gradually decreasing GABAergic synaptic transmission decreased the degree of relay neuron synchronization in response to sensory inputs, both theoretically and experimentally. Thus we have shown that lateral inhibition provides a mechanism by which the dynamic processing of odor information might be finely tuned within the OB circuit.

In the olfactory bulb (OB), odorants induce oscillations in the ␥ range (20 -80 Hz) that play an important role in the processing of sensory information. Synaptic transmission between dendrites is a major contributor to this processing. Glutamate released from mitral cell dendrites excites the dendrites of granule cells, which in turn mediate GABAergic inhibition back onto mitral cells. Although this reciprocal synapse is thought to be a key element supporting oscillatory activity, the mechanisms by which dendrodendritic inhibition induces and maintains ␥ oscillations remain unknown. Here, we assessed the role of the dendrodendritic inhibition, using mice lacking the GABA A receptor ␣1-subunit, which is specifically expressed in mitral cells but not in granule cells. The spontaneous inhibitory postsynaptic current frequency in these mutants was low and was consistent with the reduction of GABA A receptor clusters detected by immunohistochemistry. The remaining GABA A receptors in mitral cells contained the ␣3-subunit and supported slower decaying currents of unchanged amplitude. Overall, inhibitory-mediated interactions between mitral cells were smaller and slower in mutant than in WT mice, although the strength of sensory afferent inputs remained unchanged. Consequently, both experimental and theoretical approaches revealed slower ␥ oscillations in the OB network of mutant mice. We conclude, therefore, that fast oscillations in the OB circuit are strongly constrained by the precise location, subunit composition and kinetics of GABA A receptors expressed in mitral cells.␣1 knockout ͉ GABAA receptor ͉ olfaction ͉ reciprocal synapses I n the olfactory bulb (OB), ␥ frequency (20-80 Hz) oscillations of local field potentials (LFP) reflect synchronized spike discharges of principal neurons (i.e., mitral/tufted cells), and may be part of the encoding of sensory information (reviewed in refs. 1 and 2). In line with this assumption, the strength of ␥ oscillations correlates with both discrimination abilities (3) and learning capacities (4, 5) in rodents.In vivo experimental approaches revealed that ␥ oscillations are intrinsic to the OB circuitry (5-7) and are even preserved in slice preparations (8, 9), which suggests that intrinsic properties of the OB connectivity are sufficient to give rise to large-scale synchronization. Analysis of the mechanisms involved has focused almost exclusively on the excitatory principal neurons (i.e., mitral cells) and included intrinsic subthreshold oscillations (10, 11) or mutual excitation through electrical coupling and glutamate spillover between mitral cells sharing the same glomerulus (12-14). As a result, relatively little is known about the role of local inhibitory interneurons in generating and maintaining network oscillations, although pioneering studies proposed dendrodendritic inhibition as a key element for inducing fast rhythms (15)(16)(17). This assumption is also supported by the fact that interneurons constitute the main target of excitatory centrifugal fibers (18,19) k...