Reconstruction of in vivo time-evolving neuroendocrine dose–response properties unveils admixed deterministic and stochastic elements

Abstract

Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cells via quantifiable effector-response functions. On the other hand, in vivo interglandular signaling dynamics have not been estimable to date. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effectorresponse properties via a composite model comprising (i) a deterministic basic feedback and feedforward ensemble structure; (ii) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose-response properties; and (iii) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human (i) illustrates probabilistic estimation of endogenous effector dose-response properties; and (ii) unmasks statistically vivid (2-to 5-fold) random fluctuations in inferred target-gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to (i) reconstruct deterministic properties of interglandular signaling in the intact mammal and (ii) quantify apparent signal-response variability over short time scales in vivo. The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal-response relationships without isotope infusion or pathway disruption.I n contradistinction to the remarkable insights gained recently about signaling behavior in isolated systems, virtually nothing is known about quantitative properties of unperturbed interglandular control in vivo. This knowledge deficit is significant, because homeostasis in the whole organism implicitly proceeds via repeated incremental dose-responsive adjustments transduced by the exchange of inhibitory and facilitative signals (1-8). Thematic examples include reciprocal coupling between anorexigenic and satiety factors that govern body weight, sympathetic neuronal and adrenalglandular linkages that parse adaptations to stress, and glucose and insulin interactions that ration the distribution of metabolic fuels (9-11). The burgeoning repertoire of novel molecular signals establishes a need for integrative formalism to estimate such in vivo effector-response dynamics (12). The present analytical platform offers a first step toward this end. MethodsOverview. Analysis of isolated components of an interlinked system has provided important insights. However, this approach disrupts intrinsic control of spontaneously unfolding adaptive signal control. The current studies illustrate an analytical strategy to reconstruct unmanipulated in vivo dose-response attributes.Stochastic E...

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