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.