[en] Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are central to the stress response. Chemogenetic activation of PVN CRH neurons decreases LH pulse frequency but the mechanism is unknown. In the present study, optogenetic stimulation of PVN CRH neurons suppressed LH pulse frequency in estradiol-replaced ovariectomized CRH-cre mice, and this effect was augmented or attenuated by intra-PVN GABAA or GABAB receptor antagonism, respectively. PVN CRH neurons signal to local GABA neurons, which may provide a possible indirect mechanism by which PVN CRH neurons suppress LH pulse frequency. Optogenetic stimulation of potential PVN GABAergic projection terminals in the hypothalamic arcuate nucleus in ovariectomized estradiol-replaced Vgat-cre-tdTomato mice via an optic fiber implanted in the arcuate nucleus suppressed LH pulse frequency. To further determine whether PVN CRH neurons signal through PVN GABA neurons to suppress LH pulsatility, we combined recombinase mice with intersectional vectors to selectively target these neurons. CRH-cre::Vgat-FlpO mice expressing the stimulatory opsin ChRmine in non-GABAergic CRH neurons alone or in combination with the inhibitory opsin NpHR3.3 in non-CRH-expressing GABA neurons in the PVN were used. Optogenetic stimulation of non-GABAergic CRH neurons suppressed pulsatile LH secretion; however, LH pulse frequency was not affected when CRH neurons were stimulated and PVN GABA neurons were simultaneously inhibited. Together, these studies demonstrate that suppression of LH pulse frequency in response to PVN CRH neuronal activation is mediated by GABAergic signalling intrinsic to the PVN and may incorporate PVN GABAergic projection to the hypothalamic GnRH pulse generator.
Mcintyre, Caitlin ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie de la différenciation sexuelle du cerveau ; Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, SE1 1UL, UK
Li, Xiao Feng; Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, SE1 1UL, UK
Ivanova, Deyana; Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, SE1 1UL, UK
Wang, Jun; Reproductive Medicine Center, Affiliated Hospital of Guizhou Medical University, Guizhou 550004, China
O'Byrne, Kevin T ; Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, Guy's Campus, SE1 1UL, UK
Language :
English
Title :
Hypothalamic PVN CRH Neurons Signal Through PVN GABA Neurons to Suppress GnRH Pulse Generator Frequency in Female Mice.
UKRI - United Kingdom Resarch and Innovation BBSRC - Biotechnology and Biological Sciences Research Council
Funding text :
The authors are extremely grateful to Dave Layman for creating the computer program to drive the laser for optical stimulation. The authors are grateful for all the help and advice on optogenetics provided by Dr. Matt Grubb, Centre for Developmental Neurobiology, Faculty of Life Sciences and Medicine, King\u2019s College, London, UK. UKRI: BBSRC (BB/S000550/1 and BB/W005913/1).
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