A Predictive, Quantitative Model of Spiking Activity and Stimulus-Secretion Coupling in Oxytocin Neurons

Abstract

Oxytocin neurons of the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. The pattern and quantity of that release depends on the afferent inputs to the neurons, on their intrinsic membrane properties, and on nonlinear interactions between spiking activity and exocytosis: A given number of spikes will trigger more secretion when they arrive close together. Here we present a quantitative computational model of oxytocin neurons that can replicate the results of a wide variety of published experiments. The spiking model mimics electrophysiological data of oxytocin cells responding to cholecystokinin (CCK), a peptide produced in the gut after food intake. The secretion model matches results from in vitro experiments on stimulus-secretion coupling in the posterior pituitary. We mimic the plasma clearance of oxytocin with a two-compartment model, replicating the dynamics observed experimentally after infusion and injection of oxytocin. Combining these models allows us to infer, from measurements of oxytocin in plasma, the spiking activity of the oxytocin neurons that produced that secretion. We have tested these inferences with experimental data on oxytocin secretion and spiking activity in response to intravenous injections of CCK. We show how intrinsic mechanisms of the oxytocin neurons determine this relationship: In particular, we show that the presence of an afterhyperpolarization (AHP) in oxytocin neurons dramatically reduces the variability of their spiking activity and even more markedly reduces the variability of oxytocin secretion. The AHP thus acts as a filter, protecting the final product of oxytocin cells from noisy fluctuations.

The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model

“…), secretion and plasma oxytocin dynamics (Maícas Royo et al . ). To these, we added a model to mimic how osmotic pressure changes following either intravenous ( i.v. )…”

“…Here, the spiking, secretion and clearance models for oxytocin cells (Maícas Royo et al . , ) are extended to model responses to osmotic and hypovolaemic stimulation. Experimentally induced changes in osmotic pressure are mimicked by simulating the injection or infusion of i.v.…”

“…In our previous work, we used a plasma volume, Vol p , of 8.5 ml in 250 g rats (Maícas Royo et al . ), and we maintain that proportion here. Thus, initially: In simulating an injection or infusion of NaCl, the plasma volume is assumed to remain constant (the volumes infused are small relative to the EVF volume), but EVF and ICF volumes change as [Na + ] EVF changes.…”

“…This triggers a HAP and an AHP, and V evolves according to: HAP has a fixed step amplitude ( k HAP = 30 mV) and a time constant (τ HAP ) that corresponds to a half‐life of 7.5 ms, as in Maícas Royo et al . (, ). AHP has a much smaller amplitude ( k AHP = 1 mV) and τ AHP is set to correspond to a much longer half‐life of 350 ms, as previously: where δ = 1 if a spike is fired at time t , and δ = 0 otherwise.…”

“…Previously (Maícas Royo et al . ) we modelled 250 g rats, and set a fixed Vol p = 8.5 ml and a fixed Vol EVF(oxy) = 9.75 ml. Here, we defined these as a function of body weight ( B ) which varied from 190 to 400 g in the data we used: The other equations and parameter values are as in the previous work, for both the oxytocin secretion and clearance models.…”