Hosted by the Engineering Mathematics Research Group

Abstract: Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. The hypothalamic arcuate kisspeptin neurones (KNDy) are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation and controlling its dynamics remain elusive. We developed a mathematical model of the KNDy neuronal network and confirmed its predictions experimentally (in vivo) using optogenetic stimulation to mimic external inputs to the GnRH pulse generator. A key external regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region involved in processing external environmental cues, including the effect of stress. The neuronal pathways enabling the modulation of GnRH secretion remain largely unknown. We employ in silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. To this end, we develop and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD outputs on the GnRH pulse generator’s activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Based on numerical bifurcation analysis we explore these dynamics in relation to saddle–node separatrix-loop bifurcations not previously reported in neural mass models. 

Krasimira Tsaneva-Atanasova earned her undergraduate and MSc degrees in mathematics at the University of Plovdiv, Bulgaria from 1991 until 1996. In 2001 she started a PhD in applied mathematics at the University of Auckland, New Zealand. After completing her PhD in 2004 she held postdoctoral fellow positions at the Laboratory of Biological Modelling, National Institutes of Health, USA and at the Department of Mathematics and the Department of Biology at Ecole Normale Superieure in Paris, France. In 2007 she joined the Department of Engineering Mathematics at the University of Bristol as a lecturer and was promoted to a Reader in Applied Mathematics in 2012. She joined the University of Exeter in 2013 as an Associate Professor and was promoted to Professor of Mathematics for Healthcare in 2015. She has held a number of leadership roles at University of Exeter being the Associate Dean for Global in the College of Engineering, Mathematics and Physical Sciences from Aug 2018 - July 2022 and the Associate Pro-Vice Chancellor for Research and Impact in the Faculty of Environment, Science and Economy (2022-2023). Currently (since Aug 2023), she is the Vice-President and Deputy Vice-Chancellor (Research and Impact) at the University of Exeter.