A major challenge in neuroscience is relating neuronal activity to animal behavior. In olfaction limited techniques are available for these correlation studies in freely moving animals. To solve this problem, we developed an olfactory behavioral assay in head-restrained mice where we can monitor behavioral responses with high temporal precision. Mice were trained on a go/no-go operant conditioning paradigm to discriminate simple monomolecular odorants, as well as complex odorants such as binary mixtures of monomolecular odorants or natural odorants. Mice learned to discriminate both simple and complex odors in a few hundred trials with high accuracy. We then compared the discrimination performance of head-restrained mice to the performance observed in freely moving mice. Discrimination accuracies were comparable in both behavioral paradigms. In addition, discrimination times were measured while the animals performed well. In both tasks, mice discriminated simple odors in a few hundred milliseconds and took additional time to discriminate the complex mixtures. In conclusion, mice showed similar and efficient discrimination behavior while head-restrained compared with freely moving mice. Therefore, the head-restrained paradigm offers a relevant approach to monitor neuronal activity while animals are actively engaged in olfactory discrimination behaviors.

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Noradrenergic projections from the locus coeruleus (LC) project to the olfactory bulb (OB), a cortical structure implicated in odor learning and perceptual differentiation among similar odorants. We tested the role of OB noradrenaline (NA) in short-term olfactory memory using an animal model of LC degeneration coupled with intrabulbar infusions of NA. Specifically, we lesioned cortical noradrenergic fibers in mice with the noradrenergic neurotoxin N-Ethyl-N-(2-chloroethyl)-2-bromobenzylamine hydrochloride (DSP4) and measured the effects on an olfactory habituation/ spontaneous discrimination task. DSP4-treated mice failed to habituate to repeated odor presentations, indicating that they could not remember odors over the five-minute intertrial interval. We then infused NA bilaterally into the OBs of both DSP4-treated and nonlesioned control animals at two concentrations (10 −3 M and 10 −5 M, 2 ul/side). In DSP4-treated animals, NA administration at either concentration restored normal habituation and spontaneous discrimination performance, indicating that noradrenergic neuromodulation mediates these aspects of perceptual learning and that its efficacy does not require activity-dependent local regulation of NA release. Functional OB learning mechanisms may be necessary for normal odor recognition and differentiation among physically similar odorants.