The long-term goal of this research is to understand the structural and functional changes in the hypothalamus that are responsible for the reversible suppression of ovarian function, such as occurs prior to puberty. It is well recognized that increases in response to estradiol (E2) negative feedback play an important role in producing these periods of infertility (e.g., gonadostat theory of puberty). Using seasonal breeding as a model, we have identified a neural circuit (E2 responsive-neurons in the ventromedial POA [vmPOA] and the retrochiasmatic area stimulate A15 dopamine neurons to inhibit GnRH secretion) that is activated to induce the non-breeding (anestrous) season. We have recently developed strong evidence that glutamate and 3-amino butyric acid (GABA) are important controllers of A15 neural activity in anestrus. The experiments in Aim 1 will identify the GABA and glutamatergic neurons afferent to the A15 and test two specific hypotheses to account for seasonal alterations in E2 negative feedback: 1) there is a decrease in E2 receptors in GABAergic neurons during the breeding season, and 2) there is a decrease in input from E2-responsive glutamatergic afferents to the A15 during the breeding season. Studies in Aim 2 will test two alternate hypotheses to account for A15 inhibition of GnRH secretion in anestrus: 1) A15 neurons project directly to GnRH terminals in the median eminence, or 2) A15 neurons stimulate gonadotropin-inhibitory hormone (GnIH) neurons or inhibit a set of kisspeptin-containing neurons to suppress GnRH.
Aim 3 is based on evidence that thyroid hormone (T4) actions in the premammillary region and vmPOA are required for the structural changes that lead to activation of this circuit at the transition to anestrus. Specifically, we will test the hypothesis that brain-derived neurotrophic factor mediates the action of T4 during the transition to anestrus and begin to identify the down- stream targets of T4 by determining if it is necessary for seasonal changes in the number of glutamatergic synapses on to A15 neurons. We will use a combination of molecular, anatomical, pharmacological, and physiological approaches to test specific hypotheses relevant to each aim. The results of these studies will provide fundamental information on how the brain changes to shut down, and restart, fertile ovarian cycles. This information may provide novel treatments for pathological conditions, such as precocious puberty or hypothalamic ammenorrhea, in which these changes occur inappropriately. This may also provide insight into the converse situation of insufficient activity of inhibitory neural systems that appears to contribute to polycystic ovarian syndrome.

Public Health Relevance

We will use a unique animal model that enables us to examine the fundamental physiological processes that control fertility by altering the response to the negative feedback actions of estrogen. This mechanism plays a key role (123-126) in the suppression of ovarian function prior to puberty in girls (19,121), in post-partum women (122), and during lactation (124), but is poorly understood because of a paucity of useful animal models. In addition, an increased response to estrogen negative feedback has been implicated in the infertility seen in anorexia nervosa (133) and hypothalamic amenorrhea (134), and a decreased response to this action of estrogen appears to play a role in the etiology of polycystic ovarian syndrome (136).

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Lamar, Charisee A
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West Virginia University
Schools of Medicine
United States
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Nestor, Casey C; Bedenbaugh, Michelle N; Hileman, Stanley M et al. (2018) Regulation of GnRH pulsatility in ewes. Reproduction 156:R83-R99
Weems, Peyton; Smith, Jeremy; Clarke, Iain J et al. (2017) Effects of Season and Estradiol on KNDy Neuron Peptides, Colocalization With D2 Dopamine Receptors, and Dopaminergic Inputs in the Ewe. Endocrinology 158:831-841
Grachev, P; Porter, K L; Coolen, L M et al. (2016) Surge-Like Luteinising Hormone Secretion Induced by Retrochiasmatic Area NK3R Activation is Mediated Primarily by Arcuate Kisspeptin Neurones in the Ewe. J Neuroendocrinol 28:
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Weems, Peyton W; Goodman, Robert L; Lehman, Michael N (2015) Neural mechanisms controlling seasonal reproduction: principles derived from the sheep model and its comparison with hamsters. Front Neuroendocrinol 37:43-51
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Porter, K L; Hileman, S M; Hardy, S L et al. (2014) Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. J Neuroendocrinol 26:776-84
Goodman, Robert L; Hileman, Stanley M; Nestor, Casey C et al. (2013) Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology 154:4259-69
Nestor, Casey C; Coolen, Lique M; Nesselrod, Gail L et al. (2013) Evidence that orphanin FQ mediates progesterone negative feedback in the ewe. Endocrinology 154:4249-58
Merkley, Christina M; Porter, Katrina L; Coolen, Lique M et al. (2012) KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology 153:5406-14

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