Energy sufficiency is an essential requirement for optimal reproduction. Fertility is impaired in women and other female mammals when energy metabolism fails to meet bodily needs. Gonadotropin- releasing hormone (GnRH) neurons are repressed by energy shortage, but how metabolic control is asserted over this key neuroendocrine motor cell group is unclear. Our studies show that hindbrain neuroglucopenia is detected and signaled to GnRH cells by caudal dorsal vagal complex (cDVC) A2 noradrenergic neurons. This project will address the hypothesis that a discrete polysynaptic medullary- forebrain circuitry provides continuous cell energy readout to GnRH neurons, and functions as the essential framework linking body metabolism and reproduction as it integrates signals of immediate and long-range energy supply. We predict that A2 cells are first-order elements in this pathway, and energy-sensitive neurotransmitters that exert dual effects on systemic energy homeostasis and reproduction likely function downstream of these cells. This goal is impeded by the lack of analytical methods for high-resolution, multi-synaptic mapping of activated brain circuitries. This research will develop a unique high-resolution functional mapping tool to define the polysynaptic network that imposes metabolic control on GnRH, based upon micro-particle-induced X-ray emission spectrometric (PIXE) quantification of intracellular Mn+2 and application of laser-catapult microdissection and single-cell quantitative RT-PCR (qPCR) to Mn+2-permeated cells to discern phenotypic characteristics of pathway constituents.
Two specific aims will address the central hypothesis: 1) Characterize the neural network that restrains tonic reproductive neuroendocrine output during energy shortage; 2) Specific Aim 2: Determine if the A2 - GnRH pathway is a common pathway for opposing steroid-feedback and metabolic regulatory signals.
Aim 1 will examine the hypothesis that hindbrain glucopenia will elicit Mn+2 uptake by A2 neurons and trans-synaptic anterograde transport to downstream hypothalamic and preoptic (including GnRH) neurons that control reproduction, coincident with altered function of these pathway components. We assume this pathway to be a primary conduit for di- verse metabolic cues (e.g. central energy status versus peripheral energy acquisition and storage) to GnRH cells, as individual cellular elements are likely receptive to an array of hormones that embody the latter information.
Aim 2 will address the premise that energy shortage can impedes reproductive neuroendocrine output during negative and positive steroid feedback by altering respective patterns of estradiol-induced A2 signaling to GnRH neurons. We assume that energy shortage will reduce positive-feedback activation - associated Mn+2 uptake and passage through the A2- GnRH pathway, coincident with diminished pathway component function. This project will have significant impact on health through discovery of a neuroanatomical 'road-map' of functionally-connected neurochemicals that impose metabolic restraint on reproduction. Success of human and animal reproductive out- comes will be improved through delineation of potential therapeutic targets for manipulation of re- productive neuroendocrine output in disease states or complications that entail substrate fuel imbalance or energy deficit conditions due to excess metabolic demand relative to fuel availability.

Public Health Relevance

Energy balance is a key determinant of reproductive success in females. Fecundity in food and laboratory animals and women declines when energy supply cannot meet metabolic demands. Indeed, the 2006 ESHRE Workshop Group on Nutrition and Reproduction in Women notes that energy deficiency is highly correlated with reduced frequency or cessation of ovulation. Ongoing uncertainty regarding the cellular and molecular mechanisms of this critical regulatory coupling poses a significant obstacle to improvement of human and livestock reproductive outcomes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD083389-02
Application #
9015816
Study Section
Neuroscience and Ophthalmic Imaging Technologies Study Section (NOIT)
Program Officer
Lamar, Charisee A
Project Start
2015-03-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Louisiana at Monroe
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
782279541
City
Monroe
State
LA
Country
United States
Zip Code
71209
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