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Population-based signal processing and stimulus-response in oxytocin neurons

Duncan J. MacGregor, Jorge Maícas Royo and Gareth Leng

 

Presnted at the International Congress of Neuroendocrinology, Toronto 2018

 

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Computational model of a single oxytocin neuron. Spiking, secretion and plasma oxytocin dynamics

Jorge Maícas Royo, Duncan J. MacGregor and Gareth Leng

Presented at the WCNH conference 2017

 The approximately 9000 oxytocin magnocellular neurones of the rat are located in the hypothalamus. From there, they project their axons to the posterior pituitary where they secrete their products into the blood stream. The pattern and quantity of that release depends on the neuronal inputs, their spiking dynamics and on non-linear interaction between spiking activity and exocytosis: the same number of spikes will trigger more secretion when they arrive close together. Here we present a computational model for single oxytocin neurones that can replicate the spiking, secretion and plasma oxytocin dynamics from a wide variety of previously published experimental data. 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, which is a modification o an existent vasopressin secretion model [1], matches two independent in vitro experiments. We mimic the plasma clearance of oxytocin with a two-compartment model, replicating the dynamics found after infusion and injection of different oxytocin concentrations. Combining the spiking, secretion and diffusion models, we can infer the spiking activity that produces a given oxytocin concentration in plasma. These inferences match spiking data recorded during constant infusions of NaCl that linearly increase plasma osmotic pressure, or intravenous injection of CCK. In addition, we show how the presence of an after hyperpolarization potential (AHP) in oxytocin neurons dramatically reduces the variability of their spiking activity [2], but also that of oxytocin secretion and plasma levels. The AHP thus acts as a filter, protecting the final product of oxytocin cells from noisy fluctuations. 

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Osmoresponse in oxytocin neurones A predictive computational model

 Jorge Maícas Royo, Gareth Leng and Duncan J. MacGregor

Presented at tthe International Congress on Neuroendocrinology, Toronto 2018

 

In rodents and in some but not all other mammals, oxytocin responds to plasma osmotic pressure and blood volume to regulate sodium excretion at the kidneys. Oxytocin neurones respond to increases in plasma osmotic pressure partly as a result of intrinsic osmosensitivity, but also as a result of increased afferent input arising directly and indirectly from osmoreceptors in other forebrain regions. Experiments generate an osmotic challenge by injecting or infusing NaCl.
Here we present a previous computational model integrated with a new one that simulates the [Na+] dynamics in the body. To test the full model we have matched different experimental data from rats under hypertonic and hypovolemic challenges.

 

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Oxytocin single neuron dynamics. From a complete mathematical model to biological predictions.

Jorge Maicas Royo, Gareth Leng and Duncan J MacGregor

Presented at the Physiological Society meeting, Dublin

 

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Enhanced electrical activity of supraoptic neurones following systemic melanocortin administration

Luis Paiva, Nancy Sabatier, Gareth Leng, Mike Ludwig.

presented at British Society for Endocrinology. Glasgow, UK

 

Melanocortins stimulate the central oxytocin systems which regulate social behaviours1. Alterations in central oxytocin has been linked to neuropsychiatric disorders such as autism and anxiety, and melanocortins have been proposed for therapeutic treatment. Naturally occurring melanocortins including alpha-melanocyte stimulating hormone (α-MSH) potently stimulate oxytocin release from the dendrites of oxytocin cells, but inhibit their electrical activity2. α-MSH has a poor penetrance through the blood-brain barrier. Here we investigated whether Melanotan-II (MT-II), a synthetic melanocortin agonist, affects the electrical activity of supraoptic (SON) oxytocin and vasopressin neurons when given intravenously

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Ghrelin Acts in the Supramammillary Nucleus to Regulate Food Intake in Rats

Marie Le May, Nancy Sabatier, Heike Vogel, John Menzies, Gareth Leng, Suzanne L Dickson

Presented at the European College of Neuropharmacology workshop,

March 2017, Nice, France

brain with SuM
Ghrelin is an  orexigenic hormone secreted by the empty stomach before a meal. It induces food intake and food-motivated behaviour when delivered centrally or peripherally to rats.  
The supramammillary nucleus (SuM)  is located in the posterior hypothalamus and associated with food intake and food reward behaviours. Centrally delivered ghrelin binds to the SuM.

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Oxytocin single neurones. A spiking and secretion mathematical model and the role of the AHP

Jorge Maicas Royo, Duncan MacGregor, Gareth Leng

presented at the Joint Meeting of the American Physiological Society and The Physiological Society

July 2016 Dublin, Ireland


Here we show a mathematical model that mimics the spiking and secretory behavior of oxytocin neurons.  From this model, we can infer the spiking behaviour of oxytocin neurons measurements of plasma oxytocin alone. We have also revealed the physiological importance of the After Hyperpolarization (AHP) – by showing that it reduces the variability of firing rate and secretion, that it minimises the impact of small fluctuations in firing rate, and that it ensures that the secretory response to a larger challenge (like CCK) is independent of basal firing rate

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Acute Ghrelin changes food preference from high-fat diet to chow in schedule-fed rats

Tina Bake, Kim T. Hellgern and Suzanne L. Dickson

Presented at the European Obesity Summit, Stockholm, June 2106

 

Ghrelin, an orexigenic hormone released from the empty stomach, provides a gut-brain signal that promotes many appetitive behaviours,
including anticipatory and goal-directed behaviours for palatable treats high in sugar and/or fat. Here we sought to determine whether ghrelin is
able to influence and/or may even have a role in binge-like behaviour in rodents. To this end, we used a palatable scheduled feeding (PSF)
paradigm in which ad libitum chow-fed rodents are trained to “binge” on high fat diet (HFD) offered each day for a limited period of 2 hr.

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Using a single cell model to explain oxytocin neurons ability to reliably report absolute long term levels of gut peptides involved in satiety.

British Society of Neuroendocrinology, Lille, September 2015

Jorge Maícas Royo, Duncan J. MacGregor and Gareth Leng

In analysing the firing patterns of oxytocin cells in the supraoptic nucleus (SON) we noticed an unexpected feature: the mean firing rate at large binwidths is much less variable than expected from the variability at small binwidths, implying a structure in their activity that “smooths out” perturbations in activity. We have used computational modelling to determine whether this can be explained by the after-hyperpolarising potential (AHP), and if the AHP role in oxytocin cells is thus to help produce a relatively stable firing rate. However, a model of oxytocin neurons with an AHP and hyperpolarising after-potential (HAP) was not able to match both this behaviour and the interspike interval distribution. Our new model solves this by adding equations for a depolarising after potential (DAP).To test the role of the AHP with this new model, we matched recordings of five oxytocin cells exposed to apamin, a blocker of the AHP, at two concentrations. With the new model we obtain good matches for the five cells by varying only the AHP amplitude and the synaptic input rate.

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Palatable food regulates the activity of magnocellular oxytocin neurons in the supraoptic nucleus of the hypothalamus

British Society of Neuroendocrinology, Lille, September 2015

Catherine Hume, Nancy Sabatier, John Menzies & Gareth Leng

Alongside oxytocin’s classical roles in maternal behaviour, this peptide is now considered to be key in the control of food intake. In rats, there is evidence that SON oxytocin neurons are activated by the consumption of bland food when hungry. After food consumption, the peripheral hormone cholecystokinin signals satiety to anorexigenic neurons of the hypothalamic arcuate nucleus. These neurones release α-melanocyte stimulating hormone which in turn regulates oxytocin neurons in the supraoptic nucleus (SON) of the hypothalamus.

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