The overall goals of the proposed research are to determine the changes that occur in the brain during reproductive aging and to reveal the underlying mechanisms that cause a gradual decline in the regularity of the estrous cycle which is followed by a complete cessation of cyclicity in the middle-aged female rat. The central hypothesis to be tested is that while circulating estradiol levels are normal or slightly elevated in the middle-aged animals, the steroid signal does not reach the GnRH neurons which leads to a low preovulatory LH surge and to an irregular length of the estrous cycle. The present proposal focuses on the glutamatergic and noradrenergic neurotransmitter systems which have in common that they stimulate GnRH release, they are, at least in part regulated by estradiol and their activity or effectiveness are decreased in the middle-aged rat. In addition, the role of estradiol in the generation of the neuroendocrine changes associated with reproductive aging will be examined. Specifically it is proposed:
Aim 1 : to test the hypothesis that glutamate release and/or responsiveness to glutamatergic stimulation decreases during reproductive senescence;
Aim 2 : to test the hypothesis that the responsiveness of GnRH neurons to noradrenergic stimulation decreases during reproductive senescence;
Aim 3 : to test the hypothesis that life-long exposure to physiological levels of estradiol causes the malfunction in the glutamatergic and noradrenergic regulation of GnRH neurons that become apparent during reproductive senescence. The proposed studies will provide comprehensive information on the changes that occur in the regulatory input to the GnRH neurons during reproductive aging and will determine if estradiol causes these changes. A detailed knowledge of these events will help to identify some of the basic mechanisms which underlie the inappropriate interactions between the brain and the ovaries and may provide clues for treatment of disorders that are caused by a central failure to maintain adequate GnRH release.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059890-05
Application #
6639113
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Winsky, Lois M
Project Start
1999-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2005-05-31
Support Year
5
Fiscal Year
2003
Total Cost
$223,360
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Eyigor, O; Lin, W; Jennes, L (2004) Identification of neurones in the female rat hypothalamus that express oestrogen receptor-alpha and vesicular glutamate transporter-2. J Neuroendocrinol 16:26-31
Lin, Winston; McKinney, Kyle; Liu, Liansheng et al. (2003) Distribution of vesicular glutamate transporter-2 messenger ribonucleic Acid and protein in the septum-hypothalamus of the rat. Endocrinology 144:662-70
Jennes, Lothar; Lin, Wensheng; Lakhlani, Shruti (2002) Glutamatergic regulation of gonadotropin-releasing hormone neurons. Prog Brain Res 141:183-92
Temel, Sehime; Lin, Winston; Lakhlani, Shruti et al. (2002) Expression of estrogen receptor-alpha and cFos in norepinephrine and epinephrine neurons of young and middle-aged rats during the steroid-induced luteinizing hormone surge. Endocrinology 143:3974-83
Martin, Lisa J; Mahaney, Michael C; Almasy, Laura et al. (2002) Leptin's sexual dimorphism results from genotype by sex interactions mediated by testosterone. Obes Res 10:14-21
Eyigor, O; Centers, A; Jennes, L (2001) Distribution of ionotropic glutamate receptor subunit mRNAs in the rat hypothalamus. J Comp Neurol 434:101-24
Smith, M J; Jennes, L (2001) Neural signals that regulate GnRH neurones directly during the oestrous cycle. Reproduction 122:1-10
Smith, M J; Jiennes, L; Wise, P M (2000) Localization of the VIP2 receptor protein on GnRH neurons in the female rat. Endocrinology 141:4317-20
Eyigor, O; Jennes, L (2000) Kainate receptor subunit-positive gonadotropin-releasing hormone neurons express c-Fos during the steroid-induced luteinizing hormone surge in the female rat. Endocrinology 141:779-86

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