Dependence of extrasynaptic pathways on synaptic wiring

Determine whether extrasynaptic signaling pathways—specifically neuropeptidergic and other volume-transmission mechanisms—depend on synaptic wiring architecture, complement synaptic communication, or operate independently of synaptic wiring in neural systems, in order to clarify the relationship between diffusive extrasynaptic signaling and point-to-point synaptic transmission.

Background

The paper motivates its multiplex analysis by highlighting uncertainty about how extrasynaptic signaling relates to synaptic wiring. While extrasynaptic signaling is known to influence behaviors such as sleep, arousal, feeding, and homeostasis, its dependence on, complementarity with, or independence from the synaptic connectome has not been established.

To address this question within Caenorhabditis elegans, the authors construct a structure-informed functional connectome from synaptic wiring using the KMS equilibrium framework and compare it directly to the neuropeptidergic connectome, revealing distinct communication regimes. The quoted sentence frames the pre-existing uncertainty that the study aims to resolve.

References

These observations reveal that extrasynaptic communication extends beyond reinforcing synaptic circuits, but whether extrasynaptic pathways depend on, complement, or operate independently of synaptic wiring remains unresolved.

— Thermodynamic connectivity reveals functional specialization and multiplex organization of extrasynaptic signaling  (2604.02057 - Sunil et al., 2 Apr 2026) in Section 1 (Introduction)