One of the most prominent symptoms of menopause is the hot flush, a disorder of central hypothalamic thermoregulation. Despite the unprecedented numbers of individuals affected, there is little understanding of the etiology of flushes and few laboratories are studying the basic biology of this phenomenon. Hot flushes are caused by estrogen withdrawal and consist of the coordinated activation of the physiologic mechanisms to dissipate heat (cutaneous vasodilatation, sweating and behavioral changes). Integration of the hypothalamic control centers for thermoregulation and reproduction is likely to be a key element in the mechanism of flushes. In our previous studies, we described dramatic changes in the morphology and gene expression of estrogen receptor-containing NKB mRNA containing neurons in the infundibular (arcuate) nucleus of postmenopausal women. Extensive evidence gathered in animal models has shown that the increase in NKB gene expression in postmenopausal women is secondary to loss of ovarian estrogen. We hypothesize that these NKB neurons play a role in the activation of thermoregulatory vasodilatation and therefore could be involved in the generation of menopausal flushes. We have now collected substantial pilot data in support of this hypothesis and have evidence of a novel neural circuit whereby estrogen-withdrawal activates heat dissipation effectors. We postulate that estrogen-responsive NKB neurons in the rat arcuate nucleus activate thermoregulatory vasodilatation via projections to NK3 receptor- expressing neurons in the median preoptic nucleus (MnPO), an important regulatory center for autonomic function. The present proposal will focus on this hypothesis.
In specific aim 1, we will use morphologic tools to examine relationship between estrogen-responsive NKB neurons in the rat arcuate nucleus and the CNS centers controlling thermoregulatory vasodilatation.
Specific aim 2 will test the hypothesis that NK3 receptor activation of MnPO neurons stimulates heat dissipation effectors in the rat.
Specific aim 3 will evaluate whether interference with the function of NK3 receptor-expressing MnPO neurons reduces tail skin temperature or alters the thermoregulatory axis in ovariectomized rats.
Specific aim 4 will determine if NK3 receptor mRNA is expressed in neurons in the human MnPO. These studies will provide novel insights into the potential relationship between the changes in hypothalamic gene expression in postmenopausal women and the inappropriate activation of heat dissipation mechanisms that characterize the hot flush. Understanding the mechanisms of hot flushes is critical for the ultimate design of appropriate therapies. A major feature of menopause is the hot flush, which is considered to be a disorder of central nervous system thermoregulation. Hot flushes are caused by loss of estrogen and are characterized by inappropriate activation of the physiological systems that remove heat from the body (heat dissipation). Currently, no safe and efficacious treatment is available, despite the fact that hot flushes may severely impact the quality of life in many individuals. In our previous research studies, we discovered that a group of neurons expressing the peptide neurokinin B (NKB) exhibit increased gene expression in the hypothalamus of postmenopausal women. We hypothesize that these NKB neurons play a role in the physiologic mechanisms to dissipate heat and therefore could be involved in the generation of hot flushes. The present proposal is designed to test this hypothesis.

Public Health Relevance

These studies would be the first to relate the changes in hypothalamic gene expression in postmenopausal women to one of the most prominent symptoms of menopause. Little is understood about the mechanisms of hot flushes and there are only a few laboratories that study the basic biology of this problem. Understanding the mechanisms of hot flushes would greatly facilitate the design of appropriate treatments for these symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032315-02
Application #
7657321
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Mackiewicz, Miroslaw
Project Start
2008-08-01
Project End
2013-06-30
Budget Start
2009-07-15
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$277,576
Indirect Cost
Name
University of Arizona
Department
Pathology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Mittelman-Smith, Melinda A; Krajewski-Hall, Sally J; McMullen, Nathaniel T et al. (2016) Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats. Endocrinology 157:2015-27
Cholanian, M; Krajewski-Hall, S J; McMullen, N T et al. (2015) Chronic oestradiol reduces the dendritic spine density of KNDy (kisspeptin/neurokinin B/dynorphin) neurones in the arcuate nucleus of ovariectomised Tac2-enhanced green fluorescent protein transgenic mice. J Neuroendocrinol 27:253-63
Mittelman-Smith, Melinda A; Krajewski-Hall, Sally J; McMullen, Nathaniel T et al. (2015) Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat. Endocrinology 156:2552-62
Cholanian, Marina; Krajewski-Hall, Sally J; Levine, Richard B et al. (2014) Electrophysiology of arcuate neurokinin B neurons in female Tac2-EGFP transgenic mice. Endocrinology 155:2555-65
Rance, Naomi E; Dacks, Penny A; Mittelman-Smith, Melinda A et al. (2013) Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol 34:211-27
Mittelman-Smith, Melinda A; Williams, Hemalini; Krajewski-Hall, Sally J et al. (2012) Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci U S A 109:19846-51
Mittelman-Smith, Melinda A; Williams, Hemalini; Krajewski-Hall, Sally J et al. (2012) Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 153:2800-12
Dacks, Penny A; Krajewski, Sally J; Rance, Naomi E (2011) Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology 152:4894-905
Dacks, Penny A; Krajewski, Sally J; Rance, Naomi E (2011) Ambient temperature and 17*-estradiol modify Fos immunoreactivity in the median preoptic nucleus, a putative regulator of skin vasomotion. Endocrinology 152:2750-9
Dacks, Penny A; Rance, Naomi E (2010) Effects of estradiol on the thermoneutral zone and core temperature in ovariectomized rats. Endocrinology 151:1187-93

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