Endocrinology, Vol 137, 3696-3701, Copyright © 1996 by Endocrine Society

ARTICLES

In vivo antisense antagonism of vasoactive intestinal peptide in the suprachiasmatic nuclei causes aging-like changes in the estradiol- induced luteinizing hormone and prolactin surges

JP Harney, K Scarbrough, KL Rosewell and PM Wise
Department of Physiology, University of Kentucky College of Medicine, Lexington 40536-0084, USA.

In mammals, the suprachiasmatic nuclei (SCN) regulate the timing of LH surges. Recent evidence suggests that vasoactive intestinal peptide (VIP), an abundantly expressed neuropeptide of the SCN, communicates time of day information from the SCN to GnRH neurons. VIP levels in the SCN decrease with age and may be responsible for alterations in LH surges that become apparent in middle-aged rats. We wished to determine whether suppression of VIP synthesis, through antisense oligonucleotides (oligos) directed at the SCN, results in 1) selective suppression of VIP levels in the SCN and 2) aging-like changes in the secretion of LH and PRL. To test the specificity of antisense oligo treatment, rats were ovariectomized and treated with estradiol. Antisense or control random oligos were infused into the peri-SCN region through stereotaxically placed bilateral cannulas. Beginning at lights off, rats were maintained in constant dim red illumination throughout the remainder of the experiment. They were killed at specific times, brains were microdissected, and VIP concentrations in the SCN, paraventricular nuclei, and cortex were assayed. As a control for the specificity of antisense VIP treatment, we monitored the levels of arginine vasopressin in the SCN. To test the effects of antisense treatment on the pattern of plasma LH and PRL secretion, blood samples were collected from atrial catheters from 1200-2000 h, and plasma samples were assayed for LH and PRL. The results indicate that the effects of antisense treatment were discrete, as they suppressed VIP concentrations in the SCN, but had no effect on VIP concentrations in the paraventricular nuclei or cortex or on arginine vasopressin concentrations in the SCN. Peak LH levels during the surge were delayed and attenuated in antisense-treated animals compared to random oligo- treated control rats in a manner strikingly similar to that observed previously in middle-aged rats. Likewise, PRL, which was unaffected in middle-aged rats, was also unaffected by targeted suppression of VIP. In summary, our findings clearly demonstrate that antisense VIP oligos suppress VIP levels in the SCN and do not affect peptide concentrations in other regions of the brain or other neuropeptides in the SCN. Further, we show that suppression of a single neuropeptide in the SCN can mimic the effects of age on the estradiol-induced surges of LH and PRL. These data support a central role for suprachiasmatic VIP in the regulation of the LH surge and suggest that age-related perturbations in the integrity of this axis may account for alterations in the pattern of LH secretion observed during middle age.

This article has been cited by other articles:

				C. A. Christian and S. M. Moenter Vasoactive Intestinal Polypeptide Can Excite Gonadotropin-Releasing Hormone Neurons in a Manner Dependent on Estradiol and Gated by Time of Day Endocrinology, June 1, 2008; 149(6): 3130 - 3136. [Abstract] [Full Text] [PDF]

				M. O. Poletini, D. T. McKee, J. E. Kennett, J. Doster, and M. E. Freeman Knockdown of clock genes in the suprachiasmatic nucleus blocks prolactin surges and alters FRA expression in the locus coeruleus of female rats Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1325 - E1334. [Abstract] [Full Text] [PDF]

				B. H. Miller, S. L. Olson, J. E. Levine, F. W. Turek, T. H. Horton, and J. S. Takahashi Vasopressin Regulation of the Proestrous Luteinizing Hormone Surge in Wild-Type and Clock Mutant Mice Biol Reprod, November 1, 2006; 75(5): 778 - 784. [Abstract] [Full Text] [PDF]

				L. M. Gerhold and P. M. Wise Vasoactive Intestinal Polypeptide Regulates Dynamic Changes in Astrocyte Morphometry: Impact on Gonadotropin-Releasing Hormone Neurons Endocrinology, May 1, 2006; 147(5): 2197 - 2202. [Abstract] [Full Text] [PDF]

				H. O. de la Iglesia and W. J. Schwartz Minireview: Timely Ovulation: Circadian Regulation of the Female Hypothalamo-Pituitary-Gonadal Axis Endocrinology, March 1, 2006; 147(3): 1148 - 1153. [Abstract] [Full Text] [PDF]

				L. M. Gerhold, K. L. Rosewell, and P. M. Wise Suppression of Vasoactive Intestinal Polypeptide in the Suprachiasmatic Nucleus Leads to Aging-Like Alterations in cAMP Rhythms and Activation of Gonadotropin-Releasing Hormone Neurons J. Neurosci., January 5, 2005; 25(1): 62 - 67. [Abstract] [Full Text] [PDF]

				J. W. Barnes, S. A. Tischkau, J. A. Barnes, J. W. Mitchell, P. W. Burgoon, J. R. Hickok, and M. U. Gillette Requirement of Mammalian Timeless for Circadian Rhythmicity Science, October 17, 2003; 302(5644): 439 - 442. [Abstract] [Full Text] [PDF]

				P. M. Wise, M. J. Smith, D. B. Dubal, M. E. Wilson, S. W. Rau, A. B. Cashion, M. Bottner, and K. L. Rosewell Neuroendocrine Modulation and Repercussions of Female Reproductive Aging Recent Prog. Horm. Res., January 1, 2002; 57(1): 235 - 256. [Abstract] [Full Text] [PDF]

				K. Krajnak, K. L. Rosewell, and P. M. Wise Fos-Induction in Gonadotropin-Releasing Hormone Neurons Receiving Vasoactive Intestinal Polypeptide Innervation Is Reduced in Middle-Aged Female Rats Biol Reprod, April 1, 2001; 64(4): 1160 - 1164. [Abstract] [Full Text]

				B. S. Rubin Hypothalamic Alterations and Reproductive Aging in Female Rats: Evidence of Altered Luteinizing Hormone-Releasing Hormone Neuronal Function Biol Reprod, April 1, 2000; 63(4): 968 - 976. [Abstract] [Full Text]

				P. M. Wise Neuroendocrine modulation of the "menopause": insights into the aging brain Am J Physiol Endocrinol Metab, December 1, 1999; 277(6): E965 - E970. [Abstract] [Full Text] [PDF]

				K. Krajnak, M. L. Kashon, K. L. Rosewell, and P. M. Wise Sex Differences in the Daily Rhythm of Vasoactive Intestinal Polypeptide But Not Arginine Vasopressin Messenger Ribonucleic Acid in the Suprachiasmatic Nuclei Endocrinology, October 1, 1998; 139(10): 4189 - 4196. [Abstract] [Full Text] [PDF]

				K. Krajnak, M. L. Kashon, K. L. Rosewell, and P. M. Wise Aging Alters the Rhythmic Expression of Vasoactive Intestinal Polypeptide mRNA But Not Arginine Vasopressin mRNA in the Suprachiasmatic Nuclei of Female Rats J. Neurosci., June 15, 1998; 18(12): 4767 - 4774. [Abstract] [Full Text] [PDF]

				A. Cai, K. Scarbrough, D. A. Hinkle, and P. M. Wise Fetal grafts containing suprachiasmatic nuclei restore the diurnal rhythm of CRH and POMC mRNA in aging rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 1997; 273(5): R1764 - R1770. [Abstract] [Full Text] [PDF]