Modeling cooperative volume signaling in a plexus of nitric-oxide-synthase-expressing neurons

In vertebrate and invertebrate brains, nitric oxide (NO) synthase (NOS) is frequently expressed in extensive meshworks (plexuses) of exceedingly fine fibers. In this paper, we investigate the functional implications of this morphology by modeling NO diffusion in fiber systems of varying fineness and dispersal. Because size severely limits the signaling ability of an NO-producing fiber, the predominance of fine fibers seems paradoxical. Our modeling reveals, however, that cooperation between many fibers of low individual efficacy can generate an extensive and strong volume signal. Importantly, the signal produced by such a system of cooperating dispersed fibers is significantly more homogeneous in both space and time than that produced by fewer larger sources. Signals generated by plexuses of fine fibers are also better centered on the active region and less dependent on their particular branching morphology. We conclude that an ultrafine plexus is configured to target a volume of the brain with a homogeneous volume signal. Moreover, by translating only persistent regional activity into an effective NO volume signal, dispersed sources integrate neural activity over both space and time. In the mammalian cerebral cortex, for example, the NOS plexus would preferentially translate persistent regional increases in neural activity into a signal that targets blood vessels residing in the same region of the cortex, resulting in an increased regional blood flow. We propose that the fineness-dependent properties of volume signals may in part account for the presence of similar NOS plexus morphologies in distantly related animals.