The Role of KNDy Neurons in Estrogen Modulation of LH Release, Body Weight, and Thermoregulation

Persistent Link:
http://hdl.handle.net/10150/223352
Title:
The Role of KNDy Neurons in Estrogen Modulation of LH Release, Body Weight, and Thermoregulation
Author:
Smith, Melinda Anne
Issue Date:
2012
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release after 23-Mar-2013
Abstract:
Up to 80% of menopausal women suffer from hot flushes, consisting of a coordinated activation of heat loss mechanisms (sweating, cutaneous vasodilatation, etc.). Ovarian steroid withdrawal also leads to hypersecretion of gonadotropins (LH and FSH) and changes in body fat distribution. Because gonadotropin release, thermoregulation, and energy balance are hierarchically controlled by the hypothalamus, it is likely that changes in response to estrogen withdrawal are occurring at the level of the hypothalamus. The infundibular (arcuate) nucleus of the hypothalamus contains an estrogen-sensitive population of cells that co-express kisspeptin, neurokin B (NKB), and dynorphin ("KNDy neurons"). KNDy neurons have been proposed to be a site of estrogen negative feedback on gonadotropin release in multiple species because they are estrogen sensitive and respond to estrogen withdrawal with somatic hypertrophy and significant changes in gene expression. Because KNDy neurons project to known thermoregulatory centers in the hypothalamus (such as the median preoptic nucleus, MnPO), we also hypothesized that changes in thermoregulation were also a due to changes in KNDy neurons. Ovariectomized (OVX) rats also show disorders of thermoregulation, increased serum LH and FSH, and altered weight gain. Furthermore, OVX rats exhibit KNDy gene expression changes similar to changes seen in the human, making this model ideal to study the effects of estrogen withdrawal. We used a novel neurotoxin conjugate NK₃-SAP to ablate KNDy neurons in OVX female rats. We then observed core and tail skin temperatures, serum gonadotropin levels, and weight changes before and after replacement with 17β-estradiol. Next, we ablated NK3R-expressing neurons in the MnPO and monitored the thermoregulatory axis. Rats with KNDy-ablation did not exhibit the rise in LH and profound weight gain associated with ovariectomy. Furthermore, KNDy-ablated animals did not exhibit the chronic vasodilatation observed in OVX rats, providing the first evidence that KNDy neurons play a role in vasomotion. Rats with NK₃R cell-specific MnPO lesions also exhibited decreased activation of heat loss effectors. Together, these data demonstrate an important role for arcuate KNDy neurons in estrogen modulation of LH release and body weight, and demonstrate that NKB signaling is critical for activation of heat dissipation effectors.
Type:
text; Electronic Dissertation
Keywords:
Menopause; Reproduction; Thermoregulation; Neuroscience; Energy Balance; Estrogens
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Neuroscience
Degree Grantor:
University of Arizona
Advisor:
Rance, Naomi E.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe Role of KNDy Neurons in Estrogen Modulation of LH Release, Body Weight, and Thermoregulationen_US
dc.creatorSmith, Melinda Anneen_US
dc.contributor.authorSmith, Melinda Anneen_US
dc.date.issued2012-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseRelease after 23-Mar-2013en_US
dc.description.abstractUp to 80% of menopausal women suffer from hot flushes, consisting of a coordinated activation of heat loss mechanisms (sweating, cutaneous vasodilatation, etc.). Ovarian steroid withdrawal also leads to hypersecretion of gonadotropins (LH and FSH) and changes in body fat distribution. Because gonadotropin release, thermoregulation, and energy balance are hierarchically controlled by the hypothalamus, it is likely that changes in response to estrogen withdrawal are occurring at the level of the hypothalamus. The infundibular (arcuate) nucleus of the hypothalamus contains an estrogen-sensitive population of cells that co-express kisspeptin, neurokin B (NKB), and dynorphin ("KNDy neurons"). KNDy neurons have been proposed to be a site of estrogen negative feedback on gonadotropin release in multiple species because they are estrogen sensitive and respond to estrogen withdrawal with somatic hypertrophy and significant changes in gene expression. Because KNDy neurons project to known thermoregulatory centers in the hypothalamus (such as the median preoptic nucleus, MnPO), we also hypothesized that changes in thermoregulation were also a due to changes in KNDy neurons. Ovariectomized (OVX) rats also show disorders of thermoregulation, increased serum LH and FSH, and altered weight gain. Furthermore, OVX rats exhibit KNDy gene expression changes similar to changes seen in the human, making this model ideal to study the effects of estrogen withdrawal. We used a novel neurotoxin conjugate NK₃-SAP to ablate KNDy neurons in OVX female rats. We then observed core and tail skin temperatures, serum gonadotropin levels, and weight changes before and after replacement with 17β-estradiol. Next, we ablated NK3R-expressing neurons in the MnPO and monitored the thermoregulatory axis. Rats with KNDy-ablation did not exhibit the rise in LH and profound weight gain associated with ovariectomy. Furthermore, KNDy-ablated animals did not exhibit the chronic vasodilatation observed in OVX rats, providing the first evidence that KNDy neurons play a role in vasomotion. Rats with NK₃R cell-specific MnPO lesions also exhibited decreased activation of heat loss effectors. Together, these data demonstrate an important role for arcuate KNDy neurons in estrogen modulation of LH release and body weight, and demonstrate that NKB signaling is critical for activation of heat dissipation effectors.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectMenopauseen_US
dc.subjectReproductionen_US
dc.subjectThermoregulationen_US
dc.subjectNeuroscienceen_US
dc.subjectEnergy Balanceen_US
dc.subjectEstrogensen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineNeuroscienceen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorRance, Naomi E.en_US
dc.contributor.committeememberMcMullen, Nathaniel T.en_US
dc.contributor.committeememberHoyer, Patriciaen_US
dc.contributor.committeememberLai, Josephineen_US
dc.contributor.committeememberRance, Naomi E.en_US
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