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

Abstract

Key points A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus–secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments. Abstract Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co‐activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.

Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription

“…Another assumption here is the simple linear encoding between osmotic stimulus and the rate of synaptic input. Recent work in oxytocin neurons (Maícas Royo, Leng and MacGregor, 2019) modelling osmotic stimulus in more detail, to simulate experiments in which plasma oxytocin was measured in response to Na + injections or infusions, supports this. The linear encoding assumption was sufficient to closely match experimental plasma concentrations with the model, and it is reasonable to assume similar in vasopressin neurons.…”

“…Our previous work developing the vasopressin secretion model used a simple, single volume estimate of the relation between secretion rate and plasma concentration (MacGregor and Leng, 2013). More recently we adapted the secretion model to oxytocin neurons and integrated a new model of plasma diffusion and clearance (Maícas-Royo, Leng and MacGregor, 2018) which is able to accurately predict experimental measurements of oxytocin plasma concentration in response to both an acute stimulus (CCK injection, (Maícas-Royo, Leng and MacGregor, 2018)) and slower osmotic challenges (Maícas Royo, Leng and MacGregor, 2019).…”

Mathematical modelling of the oxytocin and vasopressin secretory system

“…The proper test of its quantitative fit was using different experimental data measuring the oxytocin plasma response to an excitatory osmotic stimulus, attempting to match this with no change to the model. This required a new model of how the osmotic input signal and fluid volumes respond to intra-venous or intra-peritoneal injection of saline, but it was able to closely match the output plasma signal, and develop understanding of how the plasma volume and osmo-sensitive components of the input signals interact [ 20 ].…”

Measuring oxytocin release in response to gavage: Computational modelling and assay validation

“…11 These experiments involved recording from magnocellular oxytocin neurones in anaesthetised rats. We recently published a computational model that enables predictions of plasma oxytocin concentrations to be made from electrophysiological data of the activity of oxytocin neurones, 12,13 so measuring oxytocin in response to gavage of sweetened condensed milk would both be an independent test of the conclusions from the electrophysiological studies and a test of the accuracy of predictions made from the computational model. However, first it was necessary to have an assay which could accurately measure oxytocin in small samples of rat plasma.…”