One of the basic questions of sensory neuroscience is how stimulus features are represented by changes in neuronal activity and how these changes affect perception. In olfaction, two critical features of the stimulus, odorant identity an concentration, can be independently perceived by animals. How the two are encoded independently is a long-standing unresolved question in the field. In mammals, odorants enter the nasal cavity with each respiration (sniff) and are transduced by a large repertoire of odorant receptors (ORs), each with a different response specificity and sensitivity. In the mouse, sensory neurons expressing each OR project to one or a few glomeruli in the olfactory bulb, from which each mitral/tufted cell (MTC) receives its main excitatory input. MTCs are the sole output neurons of the olfactory bulb and therefore play a central role in olfactory feature coding. The goal of the present proposal is to determine how MTCs encode odorant identity and concentration in awake animals. One general view in the field is that odorant identity can be expressed as a vector of OR (glomerular) activation across all inputs. It has been suggested that this odorant identity vector is transformed into a pattern of temporal delays (latencies) of activation across MTCs connected to different glomeruli1, 2. We propose that this can happen if odorant concentration in the nose increases gradually after inhalation onset with each sniff, and ORs with the highest affinities for a given odorant are activated earlier in the sniff cycle. If MTs inherit this temporal structuring of receptor activation, higher olfactory circuits could read thes latencies. One feature of this model is that the sequence of MTC activation provides a stable representation of odorant identity, independent of other factors such as sniff duration or concentration: changes in these factors would temporally scale the whole pattern of latencies without changing the sequence of activation (at least at the beginning of the inhalation). Consequently, a temporal shift of all MTC latencies would provide a representation for odor concentration independent of identity. Thus, both identity and concentration can be represented independently in time. Moreover, previous studies do not address whether the brain can or does read these latencies in behaving animals. The proposed research is methodologically innovative, in our opinion, because it achieves unprecedented control over the key components of olfaction: sniff monitoring, stimulus timing, individual receptor-type control, receptor-specifi M/T cell recording, awake/behaving animals. This research is conceptually innovative, in our opinion, because we 1) integrate pre-sensor physics with receptor-ligand interactions into a model which accounts for how odorant identity and concentration can be independently represented in the latencies of MTC responses, and 2) have developed an approach to test this model both in terms of encoding and readability in the same preparation, thus enabling particularly strong inferences regarding the representation and use of olfactory information in the nervous system.
A fundamental question in neuroscience is how the nervous system processes information under normal and pathological conditions. The experiments described in this proposal examine a new model for understanding how the senses encode information about the environment and how the brain ultimately decodes that information, using the olfactory system as a model. We hope that the insights from this work will lead to a better understanding of the language that neurons at multiple levels of the brain communicate with each other.
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