P083 Network Dynamics and Emergence of Synchronisation in A Population of KNDy Neurons
Saeed Farjami*1,2, Margaritis Voliotis1,2, Krasimira Tsaneva-Atanasova1,2,3
1Department of Mathematics and Statistics, University of Exeter, Exeter, United Kingdom
2Living Systems Institute, University of Exeter, Exeter, United Kingdom
3EPSRC Hub for Quantitative Modelling in Healthcare, University of Exeter, Exeter, United Kingdom
*Email: s.farjami@exeter.ac.uk
Introduction
Regulation of the reproductive axis critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator. A neuron population in hypothalamic arcuate nucleus co-expressing kisspeptin, neurokinin B and dynorphin (KNDy) plays a key role in generating and maintaining pulsatile GnRH release [1]. While previous research has characterised electrophysiological properties and firing patterns of single KNDy neurons [2], mechanisms governing their network dynamics, particularly the processes underlying synchronisation and burst generation, remain incompletely understood. Recent studies [3,4] have explored how network interactions contribute to the emergence of synchronised activity, but many aspects of the regulatory mechanisms remain elusive.
Methods
We have recently developed a biophysically realistic Hodgkin-Huxley-type model of a single KNDy neuron that incorporates comprehensive electrophysiological properties and calcium dynamics [2]. In this study, we refine this model to better capture experimentally observed features such as the current-frequency response. Building on this, we construct a computational model of a biologically realistic KNDy neuron network, incorporating both fast glutamate-mediated synaptic coupling and slower neuromodulatory interactions via neurokinin B (NKB) and dynorphin (Fig. 1). This fast-slow timescale coupling allows us to investigate the complex interplay between fast and slow synaptic dynamics in regulating network behaviour.
Results
We explore how network structure and neuronal interactions give rise to emergent bursting and synchronisation. Specifically, we assess the impact of connectivity patterns, functional heterogeneity, and glutamate signalling, as well as the distinct roles of NKB and dynorphin in shaping network dynamics. Our results reveal how different signalling pathways contribute to the initiation, maintenance, and termination of both ‘miniature’ and full synchronisation events. In particular, we show how glutamate, acting on a fast timescale, might play a crucial role in triggering synchronisation, whereas slower neuropeptide-mediated interactions via NKB and dynorphin contribute to the propagation and termination of these events.
Discussion
Our findings provide novel insights into the collective behaviour of KNDy neurons, bridging the gap between single-cell dynamics and network-level emergent dynamics. This work,building on previous studies,advances our understanding of how KNDy neuron networks generate and regulate GnRH pulsatile activity. Furthermore, our results offer testable hypotheses for experimental studies, guiding future research using state-of-the-art neurobiological techniques to validate computational predictions. In the long term, understanding KNDy network dynamics could inform the development of treatments for reproductive disorders linked to GnRH pulse generator dysfunction.
Figure 1. Figure 1: A schematic description of a network structure of KNDy neurons and their cell-cell interactions either through glutamate neurotransmitter or neurokinin B (NKB) and dynorphin neuropeptides (A) and feedback mechanisms among these agents (B) giving rise to GnRH pulses in GnRH neurons which in return dictate other hormonal pulsatility.
Acknowledgements
Gratefully, we acknowledge BBSRC for financial support of this study via grants BB/W005883/1 and BB/S019979/1.
References
[1]https://doi.org/10.1210/en.2010-0022.
[2]https://doi.org/10.7554/eLife.96691.4.
[3]https://doi.org/10.1016/j.celrep.2022.111914.
[4]https://doi.org/10.1371/journal.pcbi.1011820.
