Glutamatergic Neurokinin 3 Receptor Neurons in the Median Preoptic Nucleus Modulate Heat-Defense Pathways in Female Mice

We have proposed that arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons) contribute to hot flushes via projections to neurokinin 3 receptor (NK3R)-expressing neurons in the median preoptic nucleus (MnPO). To characterize the thermoregulatory role of MnPO NK3R neurons...

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Published in:Endocrinology (Philadelphia) 2019-04, Vol.160 (4), p.803-816
Main Authors: Krajewski-Hall, Sally J, Miranda Dos Santos, Filipa, McMullen, Nathaniel T, Blackmore, Elise M, Rance, Naomi E
Format: Article
Language:English
Subjects:
Ablation
Ambient temperature
Animals
Body Temperature Regulation - physiology
Development and progression
Dynorphin
Dynorphins - metabolism
Endocrinology
Estrogens
Female
Fluorescence
Glutamatergic transmission
Glutamic Acid - metabolism
Glutamic acid transporter
Green fluorescent protein
Hot Flashes - metabolism
Hot Temperature
Hypothalamus
Kiss1 protein
Kisspeptins - metabolism
Menopause
Mice
mRNA
Neurokinin B
Neurokinin B - metabolism
Neurokinin NK3 receptors
Neurons
Neurons - metabolism
Neurotransmission
Physiological aspects
Preoptic area
Preoptic area (medial)
Preoptic Area - metabolism
Proto-Oncogene Proteins c-fos - metabolism
Receptors, Neurokinin-3 - metabolism
Saporin
Temperature
Temperature sensation
Thermal stimuli
Toxins
Viscera
γ-Aminobutyric acid
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Summary:We have proposed that arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons) contribute to hot flushes via projections to neurokinin 3 receptor (NK3R)-expressing neurons in the median preoptic nucleus (MnPO). To characterize the thermoregulatory role of MnPO NK3R neurons in female mice, we ablated these neurons using injections of saporin toxin conjugated to a selective NK3R agonist. Loss of MnPO NK3R neurons increased the core temperature (TCORE) during the light phase, with the frequency distributions indicating a regulated shift in the balance point. The increase in TCORE in the ablated mice occurred despite changes in the ambient temperature and regardless of estrogen status. We next determined whether an acute increase in ambient temperature or higher TCORE would induce Fos in preoptic enhanced green fluorescent protein (EGFP)-immunoreactive neurons in Tacr3-EGFP mice. Fos activation was increased in the MnPO but no induction of Fos was found in NK3R (EGFP-immunoreactive) neurons. Thus, MnPO NK3R neurons are not activated by warm thermosensors in the skin or viscera and are not warm-sensitive neurons. Finally, RNAscope was used to determine whether Tacr3 (NK3R) mRNA was coexpressed with vesicular glutamate transporter 2 or vesicular γ-aminobutyric acid (GABA) transporter mRNA, markers of glutamatergic and GABAergic neurotransmission, respectively. In the MnPO, 94% of NK3R neurons were glutamatergic, but in the adjacent medial preoptic area, 97% of NK3R neurons were GABAergic. Thus, NK3R neurons in the MnPO are glutamatergic and play a role in reducing TCORE but are not activated by warm thermal stimuli (internal or external). These findings suggest that KNDy neurons modulate thermosensory pathways for heat defense indirectly via a subpopulation of glutamatergic MnPO neurons that express NK3R.
ISSN:1945-7170
0013-7227
1945-7170
DOI:10.1210/en.2018-00934