The amygdala, a key upstream regulator of the hypothalamic GnRH pulse generator

Lead Research Organisation: University of Exeter
Department Name: Mathematics


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Technical Summary

The GnRH pulse generator, the central regulator of the reproduction, comprises KNDy neurones in the hypothalamic arcuate nucleus. Stress suppresses this KNDy neural oscillator, but the underlying mechanisms are not well established. This project will focus on the amygdala, a part of the limbic brain typically associated with emotions and anxiety, which has strong projections to the KNDy system. Our discovery that kisspeptin signalling in the amygdala is an upstream regulator of GnRH pulse generator frequency, has facilitated the recent surge of interest in the amygdala's control of reproduction. We have shown in preliminary studies that amygdala kisspeptin operates through GABAergic signalling and that psychological stress-induced suppression of GnRH pulse generator is mediated by urocortin 3 in the amygdala. Recent developments in intersectional genetically encoded tools have enabled independent manipulation of a least two variables (eg. using Cre- or Flp-dependent constructs) in the same mouse. Capitalising these tools, this project will use simultaneous in-vivo optogenetic manipulation and gradient-index (GRIN) lens microendoscopic monitoring of GCaMP-expressing neurones in combination with mathematical modelling to, (i) examine the functional relationship between kisspeptin, GABA and glutamate neurocircuitry within the amygdala that underlies upstream regulation of hypothalamic GnRH pulse generator frequency, (ii) interrogate how the KNDy oscillator integrates the dynamic tone of inhibitory GABAergic and stimulatory glutamatergic output projections from the amygdala to regulate its rhythmic frequency, and (iii) determine how stress activated urocortin 3 neurones regulate the kisspeptin-GABA/glutamate neurocircuits in the amygdala to suppress GnRH pulse generator frequency. These studies will improve our understanding of how the higher-order limbic brain regulates the hypothalamic GnRH pulse generator that contributes to stress-dependent suppression of fertility.


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