RT Journal Article SR Electronic T1 Homeostatic feedback modulates the development of two-state patterned activity in a model serotonin motor circuit in Caenorhabditis elegans JF bioRxiv FD Cold Spring Harbor Laboratory SP 202507 DO 10.1101/202507 A1 Ravi, Bhavya A1 Garcia, Jessica A1 Collins, Kevin M. YR 2018 UL http://biorxiv.org/content/early/2018/05/07/202507.abstract AB Neuron activity accompanies synapse formation and maintenance, but how early circuit activity contributes to behavior development is not well understood. Here, we use the Caenorhabditis elegans egg-laying motor circuit as a model to understand how coordinated cell and circuit activity develops and drives a robust two-state behavior in adults. Using calcium imaging in behaving animals, we find the serotonergic Hermaphrodite Specific Neurons (HSNs) and vulval muscles show rhythmic calcium transients in L4 larvae before eggs are produced. HSN activity in L4 is tonic and lacks the alternating burst-firing/quiescent pattern seen in egg-laying adults. Vulval muscle activity in L4 is initially uncoordinated but becomes synchronous as the anterior and posterior muscle arms meet at HSN synaptic release sites. However, coordinated muscle activity does not require presynaptic HSN input. Using reversible silencing experiments, we show that neuronal and vulval muscle activity in L4 is not required for the onset of adult behavior. Instead, the accumulation of eggs in the adult uterus renders the muscles sensitive to HSN input. Sterilization or acute electrical silencing of the vulval muscles inhibits presynaptic HSN activity, and reversal of muscle silencing triggers a homeostatic increase in HSN activity and egg release that maintains ~12-15 eggs in the uterus. Feedback of egg accumulation depends upon the vulval muscle postsynaptic terminus, suggesting a retrograde signal sustains HSN synaptic activity and egg release. Our results show that egg-laying behavior in C. elegans is driven by a homeostat that scales serotonin motor neuron activity in response to postsynaptic muscle feedback.Significance Statement The functional importance of early, spontaneous neuron activity in synapse and circuit development is not well understood. Here we show that in the nematode C. elegans, the serotonergic Hermaphrodite Specific Neurons (HSNs) and postsynaptic vulval muscles show activity during circuit development, well before the onset of adult behavior. Surprisingly, early activity is not required for circuit development or the onset of adult behavior, and the circuit remains unable to drive egg laying until fertilized embryos are deposited into the uterus. Egg accumulation potentiates vulval muscle excitability, but ultimately acts to promote burst firing in the presynaptic HSNs during which eggs are laid. Our results suggest that mechanosensory feedback acts at three distinct steps to initiate, sustain, and terminate C. elegans egg-laying circuit activity and behavior.This work was funded by a grant from NINDS to KMC (R01 NS086932). JG was supported by the Bridge to the Baccalaureate Program (R25 GM050083). Strains used in this study have been provided to the C. elegans Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We thank Addys Bode and Michael Scheetz for technical assistance and help with strain construction. We thank James Baker, Julia Dallman, Laura Bianchi, Peter Larsson, Stephen Roper, and members of the Collins lab for helpful discussions and feedback.