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Final Report Summary - ODORLEARNINGCIRCUIT (Sensory learning-induced changes of neuronal population activity in the olfactory bulb of awake mice)

Executive summary
Sensory information is conveyed to specialized brain circuits and is translated into ensemble representations by various populations of projection neurons. Whether different channels of output neurons could form similar and stable representations in diverse behavioral contexts remains largely unknown. Here, we studied the olfactory bulb (OB), where two layers of output neurons, mitral and tufted cells (MCs and TCs respectively), jointly receive odorant information and in turn project to different target regions.
We chronically recorded the activity of MCs and TCs with two-photon Ca2+ imaging in awake head-fixed mice under different behavioral contexts. We investigated how the ensemble odor representation and discriminability by MCs and TCs may change during 1) repeated passive odor experience, where animals were simply exposed to odor stimulation over consecutive days and 2) odor discrimination learning, where animals were actively engaged in discrimination of two similar odors in a go/no-go task. We discovered state- and cell type-dependent ensemble plasticity in the OB: during passive sensory experience, both MCs and TCs displayed robust weakening of responses and constant remodeling of ensemble representation, yet with ensemble odor discriminability remaining stable. In contrast, after active sensory learning, MCs but not TCs showed significant improvement in ensemble odor discriminability, although both populations displayed constant reorganization of ensemble representation to a degree similar to that during passive odor experience. We thus uncovered a context-dependent long-term ensemble plasticity that is differentially implemented in distinct layers of output neurons within the same sensory circuit, allowing parallel transfer of non-redundant sensory information to distinct downstream centers.

Summary of objectives and main results
Collective activity of neuronal population, or neuronal ensemble representation, is proposed to be an important constituent of information processing in the brain. It has remained poorly understood, however, how the ensemble representation is maintained or modified over a long time scale (e.g. over days and beyond) by different types of output neurons. The recent advances in longitudinal and targeted large-scale recording with imaging offer the possibility to reliably track ensemble activity of identical neurons for a long time. Although several studies have addressed the stability or the plasticity of ensemble representations in various brain regions in behaving, it still remains a hot topic of debate whether different populations of output neurons could display distinct forms of plasticity in diverse behavioral contexts: when multiple groups of output neurons receive similar inputs yet project to different target regions, would they differently form and reorganize their ensemble representation depending on behavioral settings? Here we addressed this important question in the mouse olfactory bulb, where pattern separation of complex odor information takes place.
Ouput neurons in the OB (Mitral and tufted cells, MC & TC) play critical roles in olfactory information processing as well as olfactory-dependent learning. It has remained to be elucidated, however, how each output neuron population in the OB shows odor-evoked responses, and how these responses may change in the course of olfactory learning, where animals actively use odor information to guide their behavior. In this project, we employed in vivo 2-photon imaging using genetically encoded Ca2+ indicators (GECIs) to record the activity from each type of neurons in the OB. GECIs are chimera of fluorescent protein(s) and Ca2+-binding protein, and show fluorescent changes in response to Ca2+ transients evoked by action potentials in neurons. Their expression can be chronically stable as well as targeted to specific cell types by use of appropriate promoters. We combined this imaging technology with a novel odor-dependent behavioral task developed in the host lab, where animals can learn to discriminate two different sets of odors under head-fixed condition. We addressed the spatio-temporal pattern of population activity in the OB of awake mice and examine how the pattern may change in the course of olfactory learning.
Main results
We performed chronic two-photon imaging in awake head-fixed mice specifically expressing the genetically encoded Ca2+ indicator GCaMP6 in MCs and TCs. Taking advantage of the highly organized layer structure of the OB, we separately recorded activity of MCs and TCs residing in different focal planes. We investigated how the ensemble odor representation and discriminability by MCs and TCs may change over time during either repeated passive odor experience, where animals were simply exposed to odor stimulation over consecutive days and or odor discrimination learning, where animals were actively engaged in discrimination of two similar odors in a go/no-go task. We discovered, for the first time to our knowledge, state- and cell type-dependent ensemble plasticity in the OB, which we detail in the following.

1) We characterized fluorescence changes in response to passive odor exposure in individual neurons, and we report both increase (excitatory) and decrease (inhibitory) in fluorescence during (ON response) and after (OFF response) odor application in both cell types.
Although the results of this unbiased sampling are comparable to what can be observed in electrophysiological recordings, it was surprisingly overlooked in other studies using 2-photon calcium imaging in the OB. The proportion of cell-odor pairs for each response type were similar in MCs and TCs, suggesting that the overall inputs they receive in the local circuit might be indeed comparable. In summary, both populations of output neurons exhibited very similar behavior upon odor presentation.

2) We next asked how repeated passive sensory experience might alter the ensemble odor representation by MCs and TCs across days. We repeatedly applied daily the same set of odorants and imaged the response of the same cell assemblies. We found a general weakening in amplitude of both excitatory and inhibitory responses.
However, new cells were also becoming active over time. As a consequence, we found that the ensemble odor representation was constantly reorganized on a daily basis, but that the ensemble odor discriminability remained stable over time. Interestingly, this form of ensemble plasticity was similar in both populations of output neurons.

3) Finally, we examined the effect of active learning on ensemble odor representation and discriminability in MC and TC assemblies. Mice were trained to discriminate a pair of similar odors under head fixation, while population responses of MCs and TCs were imaged.
Although a plasticity of ensemble representation was again observed, it differed from the passive sensory experience state. This new form of plasticity improved odor discriminability. Surprisingly, this form of long-term ensemble plasticity was observed exclusively in the MC population but not in the TC population. Thus MCs might serve as a specialized output channel that can be trained to disambiguate similar odors depending on behavioral context.

In conclusion, we uncovered two forms of plasticity in output neurons of the mammalian OB: 1) experience-dependent and cell type-independent constant reorganization of ensemble odor representation as well as 2) active learning-dependent and MC-specific long-term improvement in ensemble odor discrimination. We propose that these plastic changes might be useful to optimize information coding in the OB.

See attached documents for illustrations and additional informations.

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