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

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    Author
    Smith, Melinda Anne
    Issue Date
    2012
    Keywords
    Menopause
    Reproduction
    Thermoregulation
    Neuroscience
    Energy Balance
    Estrogens
    Advisor
    Rance, Naomi E.
    
    Metadata
    Show full item record
    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
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Neuroscience
    Degree Grantor
    University of Arizona
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