Abstract
Reproductive aging is characterized by delayed and attenuated luteinizing hormone (LH) surges apparent in middle-aged rats. The suprachiasmatic nucleus (SCN) contains the circadian clock that is responsible for the timing of diverse neuroendocrine rhythms. Electrophysiological studies suggest vasoactive intestinal peptide (VIP) originating from the SCN excites gonadotropin-releasing hormone (GnRH) neurons and affects daily patterns of GnRH–LH release. Age-related LH surge dysfunction correlates with reduced VIP mRNA expression in the SCN and fewer GnRH neurons with VIP contacts expressing c-fos, a marker of neuronal activation, on the day of the LH surge. To determine if age-related LH surge dysfunction reflects reduced VIP availability or altered VIP responsiveness under estradiol positive feedback conditions, we assessed the effect of intracerebroventricular (icv) VIP infusion on c-fos expression in GnRH neurons and on LH release in ovariohysterectomized, hormone-primed young and middle-aged rats. Icv infusion of VIP between 1300 and 1600 h significantly advanced the time of peak LH release, increased total and peak LH release, and increased the number of GnRH neurons expressing c-fos on the day of the LH surge in middle-aged rats. Surprisingly, icv infusion of VIP in young females significantly reduced the number of GnRH neurons expressing c-fos and delayed and reduced the LH surge. These observations suggest that a critical balance of VIP signaling is required to activate GnRH neurons for an appropriately timed and robust LH surge in young and middle-aged females. Age-related LH surge changes may, in part, result from decreased availability and reduced VIP-mediated neurotransmission under estradiol positive feedback conditions.
Highlights
An appropriately timed and robust preovulatory gonadotropinreleasing hormone (GnRH)–luteinizing hormone (LH) surge in rodents requires the convergence of synchronized neurochemical and hormonal events
Vasoactive intestinal peptide (VIP) neurons located in the suprachiasmatic nucleus (SCN) project to GnRH neurons (Van der Beek et al, 1997), VIP activates GnRH neurons in a time- and estradiol-dependent fashion, and VIP receptors are expressed on GnRH neurons and on astrocytes that are in close apposition to and ensheath GnRH neurons (Smith et al, 2000; Gerhold and Wise, 2006)
LH SURGES AND HYPOTHALAMIC VIP mRNA EXPRESSION IN YOUNG AND MIDDLE-AGED RATS The estradiol benzoate (EB) and P-induced LH surge is delayed and attenuated in middle-aged rats compared to young rats (Figures 1A,B)
Summary
An appropriately timed and robust preovulatory gonadotropinreleasing hormone (GnRH)–luteinizing hormone (LH) surge in rodents requires the convergence of synchronized neurochemical and hormonal events. Available data suggest that a critical level of AVP and VIP signaling are required for appropriately timed LH pulse frequencies and induction of the LH surge under estradiol positive feedback conditions (Alexander et al, 1985; Harney et al, 1996; Krajnak et al, 1998; Palm et al, 1999; Colwell et al, 2003; Miller et al, 2006). VIP neurons located in the SCN project to GnRH neurons (Van der Beek et al, 1997), VIP activates GnRH neurons in a time- and estradiol-dependent fashion (van der Beek et al, 1994; Krajnak et al, 2001; Christian and Moenter, 2008), and VIP receptors are expressed on GnRH neurons and on astrocytes that are in close apposition to and ensheath GnRH neurons (Smith et al, 2000; Gerhold and Wise, 2006)
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