A Neural Circuit Underlying the Generation of Hot Flushes

Padilla, Stéphanie L.; Johnson, Christopher W.; Barker, Forrest D.; Patterson, Michael; Palmiter, Richard D.

doi:10.1016/j.celrep.2018.06.037

Cited by 101 publications

(120 citation statements)

References 40 publications

(49 reference statements)

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“…Cre:Cre is a Kiss1 KO as characterized elsewhere (Padilla et al, 2018). Kiss1 gene 297 was also confirmed undetectable from POA and MBH tissue (Supplement Figure 1).…”

Section: A Kiss1mentioning

confidence: 53%

“…Cre:GFP knock-in mouse (version 2) was generated from C57Bl/6 blastocysts and 295 verified at the University of Washington (Padilla et al, 2018). The homozygous version of this 296…”

Section: A Kiss1mentioning

confidence: 99%

“…A second pathway, 188 involving NKB/NK3R signaling, was also identified, when senktide (NK3R agonist) administration 189 into the MeA induced LH release in Kiss1 KO mice (Padilla et al, 2018). Thus, kisspeptin is not 190 a required mediator between NK3R activation in the MeA and LH secretion.…”

mentioning

confidence: 99%

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NKB Signaling in the Medial Amygdala Stimulates Gonadotropin Release in a Kisspeptin-Independent Manner in Female Mice

Fergani

León

Padilla

et al. 2018

Preprint

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Neurokinin B (NKB) signaling is critical for reproduction in all studied species. The existing consensus is that NKB induces GnRH release via kisspeptin (Kiss1) stimulation in the arcuate nucleus. However, the stimulatory action of NKB is dependent on circulating estrogen (E2) levels, without which, NKB inhibits LH release. Importantly, the evidence supporting the kisspeptin-dependent role of NKB, derives from models of persistent hypogonadal state [e.g. Kiss1r knockout (KO) mice], with reduced E2 levels. Here, we demonstrate that in the presence of E2, NKB signaling induces LH release in a kisspeptin-independent manner. Moreover, senktide (NKB receptor agonist) delivery to the medial amygdala (MeA) increases LH in E2-treated Kiss1 KO females (but not males or sham-treated females) similar to controls, and thus, this increase is independent of Kiss1 neurons. These results document a novel kisspeptin-independent regulatory pathway of reproductive function in females mediated by NKB-responsive neurons in the MeA.

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“…Cre:Cre is a Kiss1 KO as characterized elsewhere (Padilla et al, 2018). Kiss1 gene 297 was also confirmed undetectable from POA and MBH tissue (Supplement Figure 1).…”

Section: A Kiss1mentioning

confidence: 53%

“…Cre:GFP knock-in mouse (version 2) was generated from C57Bl/6 blastocysts and 295 verified at the University of Washington (Padilla et al, 2018). The homozygous version of this 296…”

Section: A Kiss1mentioning

confidence: 99%

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NKB Signaling in the Medial Amygdala Stimulates Gonadotropin Release in a Kisspeptin-Independent Manner in Female Mice

Fergani

León

Padilla

et al. 2018

Preprint

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“…An important health consequence of the altered NKB signaling in postmenopausal women is the dysregulation of the heat dissipation center which seems to play a critical role in the pathogenesis of hot flushes [29]. In accordance with this concept, recent studies of mice have shown that the artificial activation of arcuate nucleus KP neurons evokes a heat-dissipation response which can be sensitized by ovariectomy [30]. Within this volume, Modi and Dhillo provide a review of the growing evidence supporting antagonism of the NKB receptor (NK3R) as a potential new treatment for menopausal hot flushes [31].…”

Section: Menopausal Alterationsmentioning

confidence: 89%

New Perspectives for Anatomical and Molecular Studies of Kisspeptin Neurons in the Aging Human Brain

et al. 2019

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The human infundibular nucleus (corresponding to the rodent arcuate nucleus) serves as an important integration center for neuronal signals and hormones released by peripheral endocrine organs. Kisspeptin (KP) producing neurons of this anatomical site many of which also synthesize neurokinin B (NKB) are critically involved in sex hormone signaling to gonadotropin-releasing homone (GnRH) neurons. In recent years, the basic topography, morphology, neuropeptide content and connectivity of human KP neurons have been investigated with in situ hybridization and immunohistochemistry on post mortem tissues. These studies revealed that human KP neurons differ neurochemically from their rodent counterparts and show robust aging-related plasticity. Earlier immunohistochemical experiments also provided evidence for temporal changes in the hypothalamus of aging men whose NKB and KP neurons undergo hypertrophy, increase in number, exhibit increased neuropeptide mRNA expression and immunoreactivity and give rise to higher numbers of immunoreactive fibers and afferent contacts onto GnRH neurons. Increasing percentages of KP-expressing NKB perikarya, NKB axons and NKB inputs to GnRH neurons raise the intriguing possibility that a significant subset of NKB neurons begins to co-synthesize KP as aging proceeds. Although use of post mortem tissues is technically challenging, recently-available single-cell anatomical and molecular approaches discussed in this review article provide promising new tools to investigate the aging-related anatomical and functional plasticity of the human KP neuronal system.

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“…[1][2][3][4][5][6][7][8] Recently, however, it has been suggested that central kisspeptin signaling plays a broader role by coordinating the onset of puberty with metabolic parameters, such as nutrient sensing. [9][10][11][12][13] Here, we will discuss an additional and unexpected emerging role of Kiss1 ARC neurons in controlling whole-body skeletal homeostasis, highlighting recent studies that link both central and peripheral kisspeptin signaling to bone density and outlining important questions to be answered in this developing field (►Fig. 1).…”

mentioning

confidence: 99%

Should We Make More Bone or Not, As Told by Kisspeptin Neurons in the Arcuate Nucleus

Herber

Ingraham

2019

Semin Reprod Med

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Since its initial discovery in 2002, the neuropeptide Kisspeptin (Kiss1) has been anointed as the master regulator controlling the onset of puberty in males and females. Over the last several years, multiple groups found that Kiss1 signaling is mediated by the 7TM surface receptor GPCR54. Kiss1 mRNA is highly enriched in the basal medial and lateral subregions of the arcuate nucleus (ARC) in the medial basal hypothalamus. Thus, Kiss1ARC neurons reside in a unique anatomical location ideal for sensing and responding to circulating steroid hormones as well as nutrients. Kiss1 expression is highly responsive to fluctuations of the gonadal hormone, estrogen, with nearly 90% of Kiss1ARC neurons expressing the nuclear hormone estrogen receptor alpha (ERa). Here we review recent research that extends the function of Kiss1ARC neurons beyond the regulation of puberty and highlight their emerging, novel roles in controlling energy allocation, behavioral outputs, and sex-dependent bone remodeling in females. Indeed, some of these previously unknown functions for Kiss1 neurons are quite striking as exemplified by the remarkable increase in bone mass after manipulating estrogen signaling in Kiss1ARC neurons. Taken together, we suggest that Kiss1ARC neurons are highly sensitive to nutritional and hormonal cues that dictate energy utilization and reproduction.

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A Neural Circuit Underlying the Generation of Hot Flushes

Cited by 101 publications

References 40 publications

NKB Signaling in the Medial Amygdala Stimulates Gonadotropin Release in a Kisspeptin-Independent Manner in Female Mice

NKB Signaling in the Medial Amygdala Stimulates Gonadotropin Release in a Kisspeptin-Independent Manner in Female Mice

New Perspectives for Anatomical and Molecular Studies of Kisspeptin Neurons in the Aging Human Brain

Should We Make More Bone or Not, As Told by Kisspeptin Neurons in the Arcuate Nucleus

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