Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network

  1. Margaritis Voliotis  Is a corresponding author
  2. Xiao Feng Li
  3. Ross Alexander De Burgh
  4. Geffen Lass
  5. Deyana Ivanova
  6. Caitlin McIntyre
  7. Kevin O'Byrne
  8. Krasimira Tsaneva-Atanasova
  1. Department of Mathematics and Living Systems Institute, College of Engineering, Mathematics and Physical Sciences, University of Exeter, United Kingdom
  2. Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, United Kingdom
6 figures, 1 table and 1 additional file

Figures

Expression of arcuate nucleus (ARC) kisspeptin neurones with ChR2-mCherry in Kiss-Cre mouse.

Coronal section showing red mCherry fluorescence positive neurons in the ARC which indicates ChR2 receptor expressing kisspeptin neurones, following unilateral injection of …

Figure 2 with 2 supplements
Differential effect of optic stimulation of ARC kisspeptin neurons in estrous and diestrous Kiss-Cre mice.

(A–B) Representative examples showing LH secretion in response to no stimulation (grey bar) or sustained blue light (473 nm, 5 ms pulse width, black bar) activation of kisspeptin neurons at 5 Hz in …

Figure 2—figure supplement 1
Optogenetic stimulation of ARC kisspeptin neurons in diestrous Kiss-Cre mice using the original protocol.

(A–C) Representative examples showing LH secretion in diestrous Kiss-Cre mice over a 60 min control period followed by a 90 min period of sustained blue light (473 nm, 5 ms pulse width, black bar) …

Figure 2—figure supplement 2
Sustained optogenetic stimulation in control WT animals.

(A–B) Representative examples showing normal LH secretion in diestrous WT animals under sustained blue light (473 nm, 5 ms pulse width, black bar) activation of kisspeptin neurons at 5 Hz. *Denote …

Figure 3 with 1 supplement
Model predictions on the key mechanisms modulating the behaviour of the KNDy pulse generator across the ovarian cycle.

(A) Schematic illustration of the coarse-grained model of the ARC KNDy population. The model comprises three dynamical variables representing the average levels of Dyn and NKB secreted by the …

Figure 3—figure supplement 1
Posterior distributions of diestrus-to-estrus parameter changes inferred from data.

The behaviour of the model depends upon four parameters: (i) Dyn signalling strength; (ii) NKB signalling strength; (iii) network excitability and (iv) basal neuronal activity. For each of the four …

Effect of NMDA + AMPA receptor antagonists on pulsatile LH secretion in estrus.

Representative examples showing LH secretion in estrous mice in response to optic stimulation (5 Hz blue light, 473 nm, 5 ms pulse width) (A) and optic stimulation combined with the NMDA + AMPA …

Effect of NMDA + AMPA receptor antagonists on pulsatile LH secretion in diestrus.

Representative examples showing pulsatile LH secretion in response to ICV administration of aCSF as control (A), treatment with NMDA + AMPA receptor antagonists (AP5+ CNQX: bolus ICV injection [12 …

Figure 6 with 1 supplement
Differential effect of perturbations on the dynamics of the pulse generator.

Two-parameter (NKB signalling and network excitability) bifurcation diagram showing the region in the parameter space for which the system exhibits pulsatile dynamics (grey area). Two points …

Figure 6—figure supplement 1
Dynamic behaviour of the KNDY system as a function of dynorphin and NKB singalling.

Positive correlation in the regulation of these two parameters (see positive co-regulation arrows) allows robust control over the system’s dynamics, that is, large enough changes (regardless their …

Tables

Table 1
Model parameters values.
NoParameterDescriptionValueRef.
1dDDyn degradation rate0.25 min–1Voliotis et al., 2019
2dNNKB degradation rate0.25 min–1Voliotis et al., 2019
3dvFiring rate reset rate10 min–1Qiu et al., 2016
4kDDyn singalling strengthinferred
5kNNKB signalling strengthinferredRuka et al., 2016
6kvNetwork excitabilityinferred
7v0Maximum rate of neuronal activity increase30000 spikes min–2Qiu et al., 2016
8KDDyn IC500.3 nMYasuda et al., 1993
9KNNKB EC5032 nMSeabrook et al., 1995
10KvFiring rate for half-maximal NKB and Dyn secretion1200 spikes min–1Dutton and Dyball, 1979
11bBasal activityinferred
12eNKB-independent contribution to network excitabilityinferred

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