Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V)

Abstract

Increasing levels of circulating estradiol during the follicular phase of the ovarian cycle act on the brain to trigger a sudden and massive release of gonadotropin-releasing hormone (GnRH) that evokes the pituitary luteinizing hormone surge responsible for ovulation in mammals. The mechanisms through which estrogen is able to exert this potent "positive feedback" influence upon the GnRH neurons are beginning to be unravelled. Recent studies utilizing mouse models with global and cell-specific deletions of the different estrogen receptors (ERs) have shown that estrogen positive feedback is likely to use an indirect pathway involving the modulation of ERalpha-expressing neurons that project to GnRH neurons. Conventional tract tracing studies in rats, and experiments involving conditional pseudorabies virus tract tracing from GnRH neurons in the transgenic mouse, indicate that the dominant populations of ERalpha-expressing neuronal afferents to GnRH neurons reside in the anteroventral periventricular, median preoptic and periventricular preoptic nuclei. Together these estrogen-sensitive afferents to GnRH neurons form a periventricular continuum that can be referred to as rostral periventricular area of the third ventricle (RP3V) neurons. The neurochemical identity of some RP3V neurons has been determined and there is mounting evidence for important roles of glutamate, GABA, kisspeptin and neurotensin-expressing RP3V neurons in estrogen positive feedback. The definition of the key cluster of estrogen-sensitive neurons responsible for activating the GnRH neurons to evoke the GnRH surge (and ovulation) should be of substantial value to on-going efforts to understand the molecular and cellular basis of the estrogen positive feedback mechanism.

Figure 1

Dynamics of GnRH surge in the portal vasculature of two ovariectomized, estrogen-treated ewes. Adapted from Caraty, A., Locatelli, A. and Martin, G. B., 1989, Journal of Endocrinology. 123, 375-382 © Society for Endocrinology (1989). Reproduced by permission.

Figure 2

Schematic representation of the key pathway underlying estrogen positive feedback in the rodent. A population of neurons scattered through the anteroventral periventricular (AVPV), periventricular preoptic (PVpo) and median preoptic (MEPO) nuclei project directly to GnRH neurons and express ERα. Together, they are referred to as the rostral periventricular area of the third ventricle (RP3V) population of neurons. The pale cell is a GnRH neuron.

Figure 3

Definition of ERα-expressing neurons projecting to rostral preoptic area GnRH neurons using Cre-conditional Pseudorabies virus tract tracing. A. Neurons in the anteroventral periventricular nucleus (AVPV) projecting to GnRH neurons are defined by the expression of green fluorescent protein. Immunolabelling for ERα (red) reveals two of these neurons (arrows) to be ERα-expressing afferents to GnRH neurons. B. Schematic coronal representation of the location of neurons projecting to GnRH neurons (stars) at the level of the preoptic area (top) and anterior hypothalamic nuclei (AHA) (bottom). Filled stars represent primary afferents that express ERα. AC, anterior commissure; F, fornix; MEPO, median preoptic nucleus; PVa, periventricular nucleus, anterior hypothalamic area division. Adapted and reproduced from Neuron, Vol 52, Wintermantel TM, Campbell RE, Porteous R, Bock D, Grone HJ, Todman MG, Korach KS, Greiner E, Perez CA, Schutz G, Herbison AE, “Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility” 271-280, ©2006 with permission from Elsevier.

Figure 4

Nissl-stained coronal sections through the preoptic area of an adult female C57BL/6J mouse highlighting the three brain regions (anteroventral periventricular (AVPV), median preoptic (MEPO) and periventricular preoptic (PVpo) nuclei) in which ER-expressing neuronal afferents to GnRH neurons are found (RP3V neurons). The 40μm-thick sections are arranged in rostral to caudal order (A-F) with 40μm between sections. Scale bar = 500μm. OVLT, organum vasculosum of the lamina terminalis.