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 those with infertility conceive singe, as opposed to multiple, births, and for developing novel methods to prevent unwanted pregnancy in manners that are consistent with the acceptable social mores of most of the population, while minimizing side effects. The goal of this proposal is to increase our understanding of the generation of the central neural signal that ultimately leads to ovulation. This signal is provided by a shift in output of gonadotropin-releasing hormone (GnRH) neurons from one that is strictly episodic, producing on/off GnRH pulses that drive pituitary hormone release, to one in which GnRH release is continuously elevated for several hours. Estradiol initiates this GnRH surge, which induces the luteinizing hormone (LH) surge that subsequently triggers ovulation. To induce the GnRH surge, central estradiol action switches from negative feedback to positive feedback. Ovariectomized (OVX) mice treated with constant physiological levels of estradiol (OVX+E) undergo daily shifts from negative to positive feedback that are timed to the light-dark cycle, allowing mechanistic studies in a reduced variable model. In ovary-intact mice, this switch in estradiol feedback mode occurs on proestrus. Previous work in the daily surge model 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, these findings will be extended with experiments that range from reductionist investigation of neurobiological mechanisms to whole animal studies, all aimed at elucidating the upstream neuronal networks engaged by estradiol to regulate GnRH neurons and surge generation.
In Aim 1, we will study kisspeptin neurons in the anteroventral periventricular (AVPV) region, postulated to mediate estradiol positive feedback. We will determine how their inputs and intrinsic properties change with estradiol and time of day. We will also study how estradiol feedback alters functional connectivity between kisspeptin and GnRH neurons using paired recordings in brain slices. Preliminary data indicate firing pattern, intrinsic properties and neurotransmission to AVPV kisspeptin neurons are altered both by estradiol and/or time of day.
In Aim 2, we will study the mechanisms by which an acute stress disrupts the LH surge.
This aim will test the neurobiological mechanisms that are disrupted by stress, and determine effector cells using genetic and surgical approaches.
This aim will also expand our knowledge of mechanisms underlying the surge to the natural cycle. Preliminary data indicate a diurnal pattern to stress inhibition of surge generation, that the stress peptide corticotropin- releasing hormone inhibits GnRH neurons and that this is exacerbated by gonadal factors. Integration of the data resulting from the study of an excitatory and an inhibitory afferet network into existing knowledge will increase our understanding of the central neuronal control of ovulation by estradiol.

Public Health Relevance

Ovulation is a critical aspect of female fertility. Ovulation is controlled by an interplay between neurons within the brain, including those that produce the hormone gonadotropin-releasing hormone (GnRH), and the ovarian hormone estradiol. We are studying this interaction in normal females and how it is disrupted by factors that influence fertility, such as stress and diet. This information can be used to help treat infertility and desin novel contraceptive strategies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041469-13
Application #
8646937
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2002-02-11
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$424,605
Indirect Cost
$151,547
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Moenter, Suzanne M (2018) GnRH Neurons on LSD: A Year of Rejecting Hypotheses That May Have Made Karl Popper Proud. Endocrinology 159:199-205
Phumsatitpong, Chayarndorn; Moenter, Suzanne M (2018) Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice. Endocrinology 159:414-425
Adams, Caroline; Stroberg, Wylie; DeFazio, Richard A et al. (2018) Gonadotropin-Releasing Hormone (GnRH) Neuron Excitability Is Regulated by Estradiol Feedback and Kisspeptin. J Neurosci 38:1249-1263
Wang, Luhong; Burger, Laura L; Greenwald-Yarnell, Megan L et al. (2018) Glutamatergic Transmission to Hypothalamic Kisspeptin Neurons Is Differentially Regulated by Estradiol through Estrogen Receptor ? in Adult Female Mice. J Neurosci 38:1061-1072
Silveira, Marina A; Burger, Laura L; DeFazio, R Anthony et al. (2017) GnRH Neuron Activity and Pituitary Response in Estradiol-Induced vs Proestrous Luteinizing Hormone Surges in Female Mice. Endocrinology 158:356-366
Wagenmaker, Elizabeth R; Moenter, Suzanne M (2017) Exposure to Acute Psychosocial Stress Disrupts the Luteinizing Hormone Surge Independent of Estrous Cycle Alterations in Female Mice. Endocrinology 158:2593-2602
Greenwald-Yarnell, Megan L; Marsh, Courtney; Allison, Margaret B et al. (2016) ER? in Tac2 Neurons Regulates Puberty Onset in Female Mice. Endocrinology 157:1555-65
Wang, Luhong; DeFazio, Richard A; Moenter, Suzanne M (2016) Excitability and Burst Generation of AVPV Kisspeptin Neurons Are Regulated by the Estrous Cycle Via Multiple Conductances Modulated by Estradiol Action. eNeuro 3:
Moran, Spencer; Moenter, Suzanne M; Khadra, Anmar (2016) A unified model for two modes of bursting in GnRH neurons. J Comput Neurosci 40:297-315
Moenter, Suzanne M (2015) Leap of Faith: Does Serum Luteinizing Hormone Always Accurately Reflect Central Reproductive Neuroendocrine Activity? Neuroendocrinology 102:256-266

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