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RESEARCH ARTICLE

Interactions Between Neurotensin and GnRH Neurons in the Positive Feedback Control of GnRH/LH Secretion in the Mouse

¹University of Texas Southwestern Medical Center ²University of Washington ³University of Kentucky ⁴University of Washington School of Medicine

Submitted 15 June 2009 ; revised 23 October 2009 ; accepted in final form 23 October 2009

In female mammals, increased ovarian estradiol (E₂) secretion triggers GnRH release from neurons in the basal forebrain, which drives LH secretion from the pituitary and subsequently induces ovulation; however, the neural circuits that activate this preovulatory GnRH/LH surge remain unidentified. Neurotensin is expressed in neurons of the anteroventral periventricular nucleus (AVPV), a region thought to be critical for generating the preovulatory GnRH/LH surge. E₂ induces neurotensin (Nts) gene expression in this region, and blockade of neurotensin signaling reduces the LH surge in the rat. We postulated that neurotensin signaling plays a similar role in generating the E₂-induced GnRH/LH surge in mice. We used in situ hybridization (ISH) to determine whether E₂ induces Nts expression in the mouse and found evidence to support this proposition. Next, we determined that the neurotensin receptor (Ntsr2) is present in many GnRH-expressing neurons. Since the kisspeptin gene (Kiss1) is expressed in the AVPV and is responsive to E₂, we predicted that some neurons in this region express both Kiss1 and Nts; however, by double-label ISH, we observed no co-expression of the two mRNAs. We also postulated that Nts mRNA expression would increase in parallel with the E₂-induced LH surge and that the central (ICV) administration of neurotensin would stimulate LH secretion and activation of GnRH neurons, but found no evidence to support either of these hypotheses. Together, these findings suggest that although neurotensin neurons in the AVPV are targets for regulation by E₂, neurotensin does not appear to play a direct role in generating the GnRH/LH surge in the mouse.

reproduction; estradiol; AVPV; hypothalamus