Structured Spike Series Specify Gene Expression Patterns Science  05 Jul 2019: Vol. 365, Issue 6448, eaaw5030 DOI: 10.1126/science.aaw5030 Structured spike series specify gene expression patterns for olfactory circuit formation Ai Nakashima, et’al’ Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan. Laboratory for Animal Resource Development, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minami-machi, Chuo-ku, Kobe 650-0047, Japan. Laboratory for Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima Minami-machi, Chuo-ku, Kobe 650-0047, Japan. Center for Information and Neural Networks, National Institute of Information and Communications Technology, Suita City, Osaka 565-0871, Japan. Social Cooperation Program of Evolutional Chemical Safety Assessment System, LECSAS, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.        [paraphrase] 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. 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 receptor–specific expression patterns of axon-sorting molecules. 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. We performed calcium imaging experiments and optogenetic stimulation to address how neural activity generates olfactory receptor–specific 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. 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 receptor–specific 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.