Research Article

Structured spike series specify gene expression patterns for olfactory circuit formation

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Science  05 Jul 2019:
Vol. 365, Issue 6448, eaaw5030
DOI: 10.1126/science.aaw5030

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Temporal code underlies circuit formation

Olfactory neurons respond to various odorants according to which olfactory receptors, of many, they express. During development, axons from olfactory neurons that express the same olfactory receptor converge to share the same glomeruli. Nakashima et al. now show that, in mice, the neurons build these connections according to shared patterns of activity. When the olfactory receptor is triggered, it causes its cell not simply to fire but to fire in specific patterns. Neurons that speak the same code end up connected at the same glomerulus.

Science, this issue p. eaaw5030

Structured Abstract

INTRODUCTION

The development of precise neural circuits is initially directed by genetic programming and subsequently refined by neural activity. In the mouse olfactory system, axons from various olfactory sensory neurons expressing the same olfactory receptor converge onto a few spatially invariant glomeruli, generating the olfactory glomerular map in the olfactory bulbs. During development, olfactory receptors instruct axon sorting to form discrete glomeruli. Olfactory receptors generate a combinatorial code of axon-sorting molecules whose expression is regulated by neural activity. However, it remains unclear how neural activity induces olfactory receptorspecific expression patterns of axon-sorting molecules.

RATIONALE

The prevailing model for the activity-dependent development of neural circuits postulates an interaction between pre- and postsynaptic neurons. In Hebbian plasticity, the correlated activity of pre- and postsynaptic neurons strengthens synaptic connections, whereas uncorrelated activity or lack of activity weakens them. However, this theory does not explain activity-dependent mechanisms in olfactory map formation. Axons of olfactory sensory neurons can converge to form glomerular-like structures even in mutant mice lacking synaptic partners, suggesting another activity-dependent mechanism for glomerular segregation. The involvement of neural activity in olfactory map formation has been demonstrated by experimental suppression of neural activity. Here, we asked how neural activity is involved in the expression of axon-sorting molecules regulating glomerular segregation.

RESULTS

We performed calcium imaging experiments and optogenetic stimulation to address how neural activity generates olfactory receptorspecific expression patterns of axon-sorting molecules. Calcium imaging of olfactory sensory neurons revealed that the temporal patterns of spontaneous neuronal spikes were not spatially organized, but rather were correlated with the olfactory receptor types. Receptor substitution experiments demonstrated that olfactory receptors determine spontaneous activity patterns. Moreover, optogenetically differentiated patterns of neuronal activity induced expression of corresponding axon-sorting molecules and regulated glomerular segregation.

CONCLUSION

We have demonstrated an instructive role of neural activity in olfactory map formation. We propose an activity-dependent mechanism, different from Hebbian plasticity theory, in which specific patterns of spontaneous activity determined by the expressed olfactory receptor type contribute to generating the combinatorial code of axon-sorting molecules for olfactory receptorspecific axon sorting.

Neural activity is involved in various aspects of brain development and function. Our findings show that in the olfactory system, gene expression that regulates neural circuit formation is dependent on neural firing patterns. With this strategy, neurons can generate variation through diversifying gene expression. The pattern-dependent gene regulation may also expand beyond development to plastic changes in neural circuits throughout the lifetime.

Firing pattern–dependent olfactory map formation.

Top left: Diverse patterns of spontaneous neural activity in olfactory sensory neurons. Bottom left: A combinatorial expression pattern of axon-sorting molecules at axon termini of olfactory sensory neurons. Right: A model for activity-dependent olfactory map formation. OE, olfactory epithelium; OB, olfactory bulb. Axon-sorting molecules for glomerular segregation: red, Kirrel2 (kin of IRRE-like protein 2); green, Sema7A (semaphorin 7A); blue, PCDH10 (protocadherin 10).

Abstract

Neural circuits emerge through the interplay of genetic programming and activity-dependent processes. During the development of the mouse olfactory map, axons segregate into distinct glomeruli in an olfactory receptor (OR)–dependent manner. ORs generate a combinatorial code of axon-sorting molecules whose expression is regulated by neural activity. However, it remains unclear how neural activity induces OR-specific expression patterns of axon-sorting molecules. We found that the temporal patterns of spontaneous neuronal spikes were not spatially organized but were correlated with the OR types. Receptor substitution experiments demonstrated that ORs determine spontaneous activity patterns. Moreover, optogenetically differentiated patterns of neuronal activity induced specific expression of the corresponding axon-sorting molecules and regulated axonal segregation. Thus, OR-dependent temporal patterns of spontaneous activity play instructive roles in generating the combinatorial code of axon-sorting molecules during olfactory map formation.

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