Gene Expression Patterns for Olfactory Circuit Formation

Science  05 Jul 2019, Vol. 365, Issue 6448

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.

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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.

In the mammalian brain, the development of precise neural circuits is initially directed by intrinsic genetic programming and subsequently refined by neural activity. In the mouse olfactory system,    individual olfactory sensory neurons (OSNs) express a single gene of a functional olfactory receptor (OR) out of >1000 OR genes.    Axons from various OSNs expressing the same OR    converge onto a few spatially invariant glomeruli,    generating the olfactory glomerular map in the olfactory bulbs (OBs). The olfactory glomerular map forms through two processes: global targeting and glomerular segregation. OSN axons are first guided to approximate target regions according to gradients of axon guidance molecules and are subsequently sorted into specific glomerular structures in an activity-dependent manner.

The most prevailing model for the activity-dependent development of neural circuits postulates the 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 for axon sorting before the formation of synapses. OSN axons are capable of converging to form glomerular-like structures even in mutant mice lacking synaptic partners. These findings suggest another activity-dependent mechanism for glomerular segregation.

Hebbian plasticity explains the activity-dependent development of many neural circuits.    Synchronous firing of presynaptic neurons, such as retinal waves in the visual system, is a prerequisite for the Hebbian plastic changes. In the present study, we did not observe spatial or temporal correlations for the spontaneous activities among OSNs. Rather, spontaneous activity patterns of OSNs were uniquely correlated with OR types. We also showed that differing neural activity patterns induced the expression of different axon-sorting molecules regulating axonal segregation. On the basis of these results, we propose an activity-dependent mechanism, different from the Hebbian plasticity theory, in which specific patterns of spontaneous activity determined by the expressed ORs contribute to generate the combinatorial code of axon-sorting molecules for OR-specific glomerular segregation.

In the nervous system, neural activity is involved in various aspects of the neural development and plasticity—including cell type specification, dendritic branching, synaptic maturation, and learning and memory—through a complex program of gene regulation. Although several hundreds of genes have been identified as activity-dependent genes, their regulatory mechanisms and functions are not fully understood. In this study, we demonstrated firing pattern–dependent gene expression regulating neural circuit formation. With this strategy, neurons can generate variation through diversifying gene expression with only a single second messenger. The pattern-dependent regulation may also expand beyond development to the plasticity of neural circuits, which is the basis for learning and adapting to environmental changes throughout the lifetime.

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