Modelling the Hypothalamic Control of Growth Hormone Secretion
ABSTRACT Here, we construct a mathematical model of the hypothalamic systems that control the secretion of growth hormone (GH). The work extends a recent model of the pituitary GH system, adding representations of the hypothalamic GH-releasing hormone (GHRH) and somatostatin neurones, each modelled as a single synchronised unit. An unpatterned stochastic input drives the GHRH neurones generating pulses of GHRH release that trigger GH pulses. Delayed feedback from GH results in increased somatostatin release, which inhibits both GH secretion and GHRH release, producing an overall pattern of 3-h pulses of GH secretion that is very similar to the secretory profile observed in male rats. Rather than directly stimulating somatostatin release, GH feedback triggers a priming effect, increasing releasable stores of somatostatin. Varying this priming effect to reduce the effect of GH can reproduce the less pulsatile form of GH release observed in the female rat. The model behaviour is tested by comparison with experimental observations with a range of different experimental protocols involving GHRH injections and somatostatin and GH infusion.
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ABSTRACT: The task of the vasopressin system is homeostasis, a type of process which is fundamental to the brain's regulation of the body, exists in many different systems, and is vital to health and survival. Many illnesses are related to the dysfunction of homeostatic systems, including high blood pressure, obesity and diabetes. Beyond the vasopressin system's own importance, in regulating osmotic pressure, it presents an accessible model where we can learn how the features of homeostatic systems generally relate to their function, and potentially develop treatments. The vasopressin system is an important model system in neuroscience because it presents an accessible system in which to investigate the function and importance of, for example, dendritic release and burst firing, both of which are found in many systems of the brain. We have only recently begun to understand the contribution of dendritic release to neuronal function and information processing. Burst firing has most commonly been associated with rhythm generation; in this system it clearly plays a different role, still to be understood fully.Bio Systems 03/2013; 112(2). DOI:10.1016/j.biosystems.2013.03.010 · 1.47 Impact Factor
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ABSTRACT: Vasopressin neurons generate distinctive phasic patterned spike activity in response to elevated extracellular osmotic pressure. These spikes are generated in the cell body and are conducted down the axon to the axonal terminals where they trigger Ca(2+) entry and subsequent exocytosis of hormone-containing vesicles and secretion of vasopressin. This mechanism is highly non-linear, subject to both frequency facilitation and fatigue, such that the rate of secretion depends on both the rate and patterning of the spike activity. Here we used computational modelling to investigate this relationship and how it shapes the overall response of the neuronal population. We generated a concise single compartment model of the secretion mechanism, fitted to experimentally observed profiles of facilitation and fatigue, and based on representations of the hypothesised underlying mechanisms. These mechanisms include spike broadening, Ca(2+) channel inactivation, a Ca(2+) sensitive K(+) current, and releasable and reserve pools of vesicles. We coupled the secretion model to an existing integrate-and-fire based spiking model in order to study the secretion response to increasing synaptic input, and compared phasic and non-phasic spiking models to assess the functional value of the phasic spiking pattern. The secretory response of individual phasic cells is very non-linear, but the response of a heterogeneous population of phasic cells shows a much more linear response to increasing input, matching the linear response we observe experimentally, though in this respect, phasic cells have no apparent advantage over non-phasic cells. Another challenge for the cells is maintaining this linear response during chronic stimulation, and we show that the activity-dependent fatigue mechanism has a potentially useful function in helping to maintain secretion despite depletion of stores. Without this mechanism, secretion in response to a steady stimulus declines as the stored content declines.PLoS Computational Biology 08/2013; 9(8):e1003187. DOI:10.1371/journal.pcbi.1003187 · 4.83 Impact Factor