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Central Actions of Estrogens: Effects on GnRH Neurons

Award Number: R01HD041469
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/11/2002
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Central Actions of Estrogens: Effects on GnRH Neurons - Between 15 and 20% of couples have difficulty conceiving; failures of the reproductive system thus affect many individuals. In females, understanding the control of ovulation is critical for helping infertility patients conceive single vs multiple births while minimizing side effects. Psychosocial stress interferes with homeostasis and disrupts many physiologic systems including reproduction. Completing this research will help us understand how the brain responds to ovarian estradiol to generate the central neural signal that ultimately leads to ovulation and how stress disrupts this. The signal for ovulation is provided by a change in the output of gonadotropin-releasing hormone (GnRH) neurons from strictly episodic, producing on/off GnRH pulses that drive pituitary hormone release, to a surge mode in which GnRH release is continuously elevated for hours. To induce the GnRH surge, estradiol action switches from negative to positive feedback. Ovariectomized (OVX) mice treated with constant physiologic levels of estradiol (OVX+E) undergo daily shifts from negative to positive feedback that are timed to the light-dark cycle, allowing mechanistic studies of estradiol action in a reduced variable model. In cycling ovary-intact mice, this switch in estradiol feedback mode occurs on proestrus. Our previous work indicates cyclical changes in estradiol induce cycle-dependent changes in the properties of the hypothalamic neurons involved in generating the GnRH surge. This work established several mechanisms engaged by estradiol that would lead to suppression of GnRH neurons during negative feedback and activation of these cells during positive feedback. In the proposed work, we will expand upon this base in experiments that range from continued investigation of neurobiological mechanisms to whole animal studies, all aimed at elucidating estradiol feedback and GnRH surge generation, and the effects of stress on this system. In Aim 1, we will study estradiol modulation of three important circuits: from kisspeptin neurons in the anteroventral periventricular (AVPV) nucleus to GnRH neurons, from arcuate kisspeptin to AVPV kisspeptin neurons, and among AVPV kisspeptin neurons. These experiments will move us towards understanding a more complete reproductive neuroendocrine network by studying how synaptic properties are modulated by estradiol. In Aim 2, we will study the mechanisms by which acute stress exposure in adulthood perturbs the shift from estradiol negative to positive feedback, disrupting the LH surge. We will test involvement of the adrenal glands and of neurons producing corticotropin-releasing hormone (CRH). We will examine how acute stress mechanistically changes estradiol positive feedback effects on GnRH neurons. Finally, we will test how the stress neuroendocrine axis interacts with the reproductive neuroendocrine axis by examining connectivity between CRH and GnRH neurons and CRH and kisspeptin neurons and their modulation by estradiol. These studies will increase our understanding of the hypothalamic networks regulating reproductive function and how disturbances of homeostasis can interfere with the normal operation of these networks.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $422,255 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	002	24	4/30/2025	NON-COMPETING CONTINUATION	$422,255
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	001	22	2/25/2025	COMPETING CONTINUATION	$100,221
2025	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	21	2/25/2025	NON-COMPETING CONTINUATION	-$100,221
														Subtotal = $422,255

Issue Date FY: 2024 ( Subtotal = $423,343 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	23	5/21/2024	NON-COMPETING CONTINUATION	$423,343
														Subtotal = $423,343

Issue Date FY: 2023 ( Subtotal = $440,366 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	22	7/27/2023	COMPETING CONTINUATION	$440,366
														Subtotal = $440,366

Issue Date FY: 2022 ( Subtotal = $454,143 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	21	8/18/2022	NON-COMPETING CONTINUATION	$454,143
														Subtotal = $454,143

Issue Date FY: 2021 ( Subtotal = $454,559 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	20	8/12/2021	NON-COMPETING CONTINUATION	$454,559
														Subtotal = $454,559

Issue Date FY: 2020 ( Subtotal = $464,815 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	19	8/14/2020	NON-COMPETING CONTINUATION	$464,815
														Subtotal = $464,815

Issue Date FY: 2019 ( Subtotal = $465,764 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	002	18	8/27/2019	NON-COMPETING CONTINUATION	$465,764
2019	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	001	17	1/9/2019	COMPETING CONTINUATION	$20,553
2019	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	16	1/9/2019	NON-COMPETING CONTINUATION	-$20,553
														Subtotal = $465,764

Issue Date FY: 2018 ( Subtotal = $466,686 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	001	17	9/22/2018	COMPETING CONTINUATION	$454,957
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	002	17	9/25/2018	COMPETING CONTINUATION	$11,729
2018	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	16	9/21/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,686

Issue Date FY: 2017 ( Subtotal = $436,837 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	001	16	6/13/2017	NON-COMPETING CONTINUATION	$43,684
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	16	4/3/2017	NON-COMPETING CONTINUATION	$393,153
														Subtotal = $436,837

Issue Date FY: 2016 ( Subtotal = $432,467 )
2016	2016	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	15	3/10/2016	EXTENSION WITH OR WITHOUT FUNDS	$432,467
														Subtotal = $432,467

Issue Date FY: 2015 ( Subtotal = $425,916 )
2015	2015	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	14	3/17/2015	NON-COMPETING CONTINUATION	$425,916
														Subtotal = $425,916

Issue Date FY: 2014 ( Subtotal = $424,605 )
2014	2014	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	13	3/26/2014	NON-COMPETING CONTINUATION	$424,605
														Subtotal = $424,605

Issue Date FY: 2013 ( Subtotal = $459,613 )
2013	2013	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	000	12	4/5/2013	COMPETING CONTINUATION	$459,613
														Subtotal = $459,613

Issue Date FY: 2011 ( Subtotal = $249,508 )
2011	2011	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	002	11	3/29/2011	NON-COMPETING CONTINUATION	$229,186
2011	2011	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	003	11	6/13/2011	NON-COMPETING CONTINUATION	$15,280
2011	2010	UNIVERSITY OF MICHIGAN	3003 S STATE ST 3089 WOLVERINE	ANN ARBOR	MI	48109	WASHTENAW	USA	Child Health and Human Development Extramural Research	001	10	3/9/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$259,694
2011	2010	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	9	3/9/2011	NON-COMPETING CONTINUATION	-$254,652
														Subtotal = $249,508

Issue Date FY: 2010 ( Subtotal = $254,652 )
2010	2010	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	9	3/29/2010	NON-COMPETING CONTINUATION	$254,652
														Subtotal = $254,652

Issue Date FY: 2009 ( Subtotal = $257,224 )
2009	2009	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	8	4/3/2009	NON-COMPETING CONTINUATION	$257,224
														Subtotal = $257,224

Issue Date FY: 2008 ( Subtotal = $257,224 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	7	3/28/2008	NON-COMPETING CONTINUATION	$257,224
														Subtotal = $257,224

Issue Date FY: 2007 ( Subtotal = $262,474 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Child Health and Human Development Extramural Research	000	6	3/31/2007	COMPETING CONTINUATION	$262,474
														Subtotal = $262,474

Issue Date FY: 2006 ( Subtotal = $257,805 )
2006	2006	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Population Research	000	5	11/28/2005	NON-COMPETING CONTINUATION	$257,805
														Subtotal = $257,805

Issue Date FY: 2005 ( Subtotal = $264,010 )
2005	2005	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Population Research	000	4	12/28/2004	NON-COMPETING CONTINUATION	$264,010
														Subtotal = $264,010

Grand Total All Awards = $8,402,459

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Central Actions of Estrogens: Effects on GnRH Neurons

Award Number: R01HD041469

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/11/2002

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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