Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription
- 1Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom
Abstract
Hypothalamic vasopressin neurons are neuroendocrine cells which form part of the homeostatic systems that regulate plasma volume and extracellular fluid osmolarity. In response to synaptic inputs encoding osmolarity and changes in plasma volume, they generate complex and dynamically heterogeneous patterns of spikes that in turn trigger secretion of peptide hormone vasopressin from axonal terminals in the posterior pituitary. The thousands of neurons’ secretory signals generate a summed plasma vasopressin signal acting at the kidneys to regulate water loss. Vasopressin is synthesised in the neuronal cell bodies, packaged into vesicles, and transported to large stores at the pituitary terminals. Supported by activity-dependent upregulation of synthesis and transport, these stores can maintain a secretion response for several days of elevated osmolarity, experimentally tested by dehydration or salt loading. However, despite upregulated synthesis, stores gradually decline during sustained challenge, followed by a slow recovery. With no evidence of a store encoding feedback signal, previous simple modelling explained these synthesis dynamics based on activity-dependent upregulation of transcription and mRNA content. Here we integrate this idea into a detailed neuronal model, coupling spiking, secretion, and synthesis to simulate a complete neural system, from physiological input to output, and ask how a distributed neuroendocrine system can maintain hormone supply-demand balance over prolonged challenge without direct feedback from distant hormone stores. The model suggests that mRNA acts as a long-timescale memory of neuronal activity, extending temporal integration beyond spike activity and intracellular Ca2+ to coordinate synthesis with sustained demand. Author summary: In response to increases in plasma [Na+], magnocellular vasopressin neurons typically generate intermittent trains of action potentials (spikes) in a complex ‘phasic’ pattern. These patterns are asynchronous amongst vasopressin neurons, and differ considerably between cells, reflecting multiple heterogeneities in intrinsic membrane properties. The spike activity is coupled to vasopressin secretion from neuronal terminals in the posterior pituitary, and this coupling also has complex non-linearities, yet the overall secretion of vasopressin from the pituitary in response to raised plasma [Na+] is remarkably linear over a wide dynamic range. Moreover, when necessary, this system must remain functional over days of sustained hypernatraemic challenge; even as the pituitary stores of vasopressin fall dramatically. Here we have built a model of the vasopressin system, modelling not just the processes of spike generation in a heterogeneous population, and stimulus-secretion coupling, but also the depletion of store content and the regulation of vasopressin synthesis to better understand how this system maintains functionality in the face of sustained challenge.
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BibTeX
@article{macgregor2026modelling,
title = {{Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription}},
author = {Duncan J. MacGregor},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014832},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014832},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Modelling vasopressin synthesis and storage dynamics during prolonged osmotic challenge and recovery based on activity dependent upregulation of mRNA transcription
AU - Duncan J. MacGregor
PY - 2026
DA - 2026/09/30
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014832
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014832
AB - Hypothalamic vasopressin neurons are neuroendocrine cells which form part of the homeostatic systems that regulate plasma volume and extracellular fluid osmolarity. In response to synaptic inputs encoding osmolarity and changes in plasma volume, they generate complex and dynamically heterogeneous patterns of spikes that in turn trigger secretion of peptide hormone vasopressin from axonal terminals in the posterior pituitary. The thousands of neurons’ secretory signals generate a summed plasma vasopressin signal acting at the kidneys to regulate water loss. Vasopressin is synthesised in the neuronal cell bodies, packaged into vesicles, and transported to large stores at the pituitary terminals. Supported by activity-dependent upregulation of synthesis and transport, these stores can maintain a secretion response for several days of elevated osmolarity, experimentally tested by dehydration or salt loading. However, despite upregulated synthesis, stores gradually decline during sustained challenge, followed by a slow recovery. With no evidence of a store encoding feedback signal, previous simple modelling explained these synthesis dynamics based on activity-dependent upregulation of transcription and mRNA content. Here we integrate this idea into a detailed neuronal model, coupling spiking, secretion, and synthesis to simulate a complete neural system, from physiological input to output, and ask how a distributed neuroendocrine system can maintain hormone supply-demand balance over prolonged challenge without direct feedback from distant hormone stores. The model suggests that mRNA acts as a long-timescale memory of neuronal activity, extending temporal integration beyond spike activity and intracellular Ca2+ to coordinate synthesis with sustained demand. Author summary: In response to increases in plasma [Na+], magnocellular vasopressin neurons typically generate intermittent trains of action potentials (spikes) in a complex ‘phasic’ pattern. These patterns are asynchronous amongst vasopressin neurons, and differ considerably between cells, reflecting multiple heterogeneities in intrinsic membrane properties. The spike activity is coupled to vasopressin secretion from neuronal terminals in the posterior pituitary, and this coupling also has complex non-linearities, yet the overall secretion of vasopressin from the pituitary in response to raised plasma [Na+] is remarkably linear over a wide dynamic range. Moreover, when necessary, this system must remain functional over days of sustained hypernatraemic challenge; even as the pituitary stores of vasopressin fall dramatically. Here we have built a model of the vasopressin system, modelling not just the processes of spike generation in a heterogeneous population, and stimulus-secretion coupling, but also the depletion of store content and the regulation of vasopressin synthesis to better understand how this system maintains functionality in the face of sustained challenge.
SN - 1553-7358
ER -