Catherine A Christian

University of Virginia, Charlottesville, VA, United States

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Publications (8)57.99 Total impact

  • Catherine A Christian, Suzanne M Moenter
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    ABSTRACT: Ovarian steroids normally exert homeostatic negative feedback on GnRH release. During sustained exposure to elevated estradiol in the late follicular phase of the reproductive cycle, however, the feedback action of estradiol switches to positive, inducing a surge of GnRH release from the brain, which signals the pituitary LH surge that triggers ovulation. In rodents, this switch appears dependent on a circadian signal that times the surge to a specific time of day (e.g., late afternoon in nocturnal species). Although the precise nature of this daily signal and the mechanism of the switch from negative to positive feedback have remained elusive, work in the past decade has provided much insight into the role of circadian/diurnal and estradiol-dependent signals in GnRH/LH surge regulation and timing. Here we review the current knowledge of the neurobiology of the GnRH surge, in particular the actions of estradiol on GnRH neurons and their synaptic afferents, the regulation of GnRH neurons by fast synaptic transmission mediated by the neurotransmitters gamma-aminobutyric acid and glutamate, and the host of excitatory and inhibitory neuromodulators including kisspeptin, vasoactive intestinal polypeptide, catecholamines, neurokinin B, and RFamide-related peptides, that appear essential for GnRH surge regulation, and ultimately ovulation and fertility.
    Endocrine reviews 03/2010; 31(4):544-77. · 19.76 Impact Factor
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    ABSTRACT: A surge of gonadotropin-releasing hormone (GnRH) release from the brain triggers the luteinizing hormone (LH) surge that causes ovulation. The GnRH surge is initiated by a switch in estradiol action from negative to positive feedback. Estradiol signals critical for the surge are likely transmitted to GnRH neurons at least in part via estradiol-sensitive afferents. Using an ovariectomized estradiol-treated (OVX+E) mouse model that exhibits daily LH surges, we examined changes in glutamate transmission to GnRH neurons during negative feedback and positive feedback. Spontaneous glutamatergic excitatory postsynaptic currents (EPSCs) mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptors (AMPA/KA Rs) or N-methyl-D-aspartate receptors (NMDARs) were recorded in GnRH neurons from OVX+E and OVX mice. There were no diurnal changes in the percentage of GnRH neurons from OVX mice exhibiting EPSCs. In cells from OVX+E mice, the profile of AMPA/KA R-mediated and NMDAR-mediated EPSCs showed changes dependent on time of day. Comparison of AMPA/KA R-mediated EPSC frequency in OVX+E and OVX cells showed that estradiol suppressed transmission during negative feedback but had no effect during positive feedback. Tetrodotoxin treatment to block action potential firing did not affect AMPA/KA R-mediated EPSC frequency in OVX cells during negative feedback or in OVX+E cells during positive feedback, suggesting that estradiol-induced suppression of glutamate transmission may be primarily due to activity-independent changes. The diurnal removal of estradiol-induced suppression of AMPA/KA R-mediated glutamate transmission to GnRH neurons during positive feedback suggests that the primary role for estradiol-induced changes in glutamate transmission may be in mediating negative feedback.
    Biology of Reproduction 02/2009; 80(6):1128-35. · 4.03 Impact Factor
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    S M Moenter, Z Chu, C A Christian
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    ABSTRACT: The feedback actions of ovarian oestradiol during the female reproductive cycle are among the most unique in physiology. During most of the cycle, oestradiol exerts homeostatic, negative feedback upon the release of gonadotrophin-releasing hormone (GnRH). Upon exposure to sustained elevated oestradiol levels, however, there is a switch in the feedback effects of this hormone to positive, resulting in induction of a surge in the release of GnRH that serves as a neuroendocrine signal to initiate the ovulatory cascade. We review recent developments stemming from studies in an animal model exhibiting daily switches between positive and negative feedback that have probed the neurobiological mechanisms, including changes in neural networks and intrinsic properties of GnRH neurones, underlying this switch in oestradiol action.
    Journal of Neuroendocrinology 02/2009; 21(4):327-33. · 3.33 Impact Factor
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    ABSTRACT: During the female reproductive cycle, the neuroendocrine action of estradiol switches from negative feedback to positive feedback to initiate the preovulatory GnRH and subsequent LH surges. Estrogen receptor-alpha (ERalpha) is required for both estradiol negative and positive feedback regulation of LH. ERalpha may signal through estrogen response elements (EREs) in DNA and/or via ERE-independent pathways. Previously, a knock-in mutant allele (ERalpha-/AA) that selectively restores ERE-independent signaling onto the ERalpha-/- background was shown to confer partial negative but not positive estradiol feedback on serum LH. The current study investigated the roles of the ERE-dependent and ERE-independent ERalpha pathways for estradiol feedback at the level of GnRH neuron firing activity. The above ERalpha genetic models were crossed with GnRH-green fluorescent protein mice to enable identification of GnRH neurons in brain slices. Targeted extracellular recordings were used to monitor GnRH neuron firing activity using an ovariectomized, estradiol-treated mouse model that exhibits diurnal switches between negative and positive feedback. In wild-type mice, GnRH neuron firing decreased in response to estradiol during negative feedback and increased during positive feedback. In contrast, both positive and negative responses to estradiol were absent in GnRH neurons from ERalpha-/- and ERalpha-/AA mice. ERE-dependent signaling is thus required to increase GnRH neuron firing to generate a GnRH/LH surge. Furthermore, ERE-dependent and -independent ERalpha signaling pathways both appear necessary to mediate estradiol negative feedback on serum LH levels, suggesting central and pituitary estradiol feedback may use different combinations of ERalpha signaling pathways.
    Endocrinology 11/2008; 149(11):5328-34. · 4.72 Impact Factor
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    Catherine A Christian, Suzanne M Moenter
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    ABSTRACT: A switch in the balance of estradiol feedback actions from negative to positive initiates the GnRH surge, triggering the LH surge that causes ovulation. Using an ovariectomized, estradiol-treated (OVX+E) mouse model that exhibits daily switches between negative in the morning and positive feedback in the evening, we investigated the roles of fast synaptic transmission in regulating GnRH neuron firing during negative and positive feedback. Targeted extracellular recordings were used to monitor activity of GnRH neurons from OVX+E and OVX mice in control solution or solution with antagonists to both ionotropic glutamate and gamma-aminobutyric acid receptors (blockade). Blockade had no effect on activity of OVX cells. In contrast, in OVX+E cells in the morning, blockade increased activity compared with control cells, whereas in the evening, blockade decreased activity. In vivo barbiturate sedation of OVX+E mice that blocked LH surge induction prevented the in vitro evening changes in firing rate and response to blockade. These observations suggest at least partial inversion of the negative-to-positive switch in estradiol feedback action and indicate that changes in fast synaptic transmission to GnRH neurons and within the network of cells presynaptic to GnRH neurons are critical for mediating estradiol negative and positive feedback actions on GnRH neurons. Fast synaptic transmission may also affect GnRH neuron activity indirectly through altering release of excitatory and inhibitory neuromodulators onto GnRH neurons at specific times of day. Fast synaptic transmission is thus critical for proper generation and timing of the GnRH surge.
    Endocrinology 08/2008; 149(11):5500-8. · 4.72 Impact Factor
  • Catherine A Christian, Suzanne M Moenter
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    ABSTRACT: A surge of GnRH release signals the LH surge that triggers ovulation. The GnRH surge is dependent on a switch in estradiol feedback from negative to positive and, in rodents, a daily neural signal, likely from the suprachiasmatic nuclei. Vasoactive intestinal polypeptide (VIP) may be involved in suprachiasmatic nuclei-GnRH neuron communication. Here we assessed the effects of acute VIP (5 min treatment) on GnRH neuron function using targeted extracellular recordings of firing activity of GnRH neurons in brain slices. We examined the effect of VIP on firing rate at different times of day using an established ovariectomized, estradiol-treated (OVX+E) mouse model that exhibits daily LH surges timed to the late afternoon. Cells from OVX animals (no estradiol) did not respond to VIP, regardless of time of day. With estradiol, the effect of VIP on GnRH neurons was dependent on the time of recording. During negative feedback, OVX+E cells did not respond. VIP increased firing in cells recorded during surge onset, but this excitatory response was reduced at surge peak. Acute treatment of OVX+E cells during surge peak with a VIP receptor antagonist decreased GnRH neuron firing. This suggests endogenous VIP may both increase GnRH neuron firing during the surge and occlude response to exogenous VIP. These data provide functional evidence for VIP effects on GnRH neurons and indicate that both estradiol and time of day gate the GnRH neuron response to this peptide. VIP may provide an excitatory signal from the circadian clock that helps time the GnRH surge.
    Endocrinology 07/2008; 149(6):3130-6. · 4.72 Impact Factor
  • Catherine A Christian, Suzanne M Moenter
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    ABSTRACT: Ovulation is initiated by a surge of gonadotropin-releasing hormone (GnRH) secretion by the brain. GnRH is normally under negative feedback control by ovarian steroids. During sustained exposure to estradiol in the late follicular phase of the reproductive cycle, however, the feedback action of this steroid switches to positive, inducing the surge. Here, we used an established ovariectomized, estradiol-treated (OVX+E) mouse model exhibiting daily surges to investigate the neurobiological mechanisms underlying this switch. Specifically, we examined changes in GABA transmission to GnRH neurons, which can be excited by GABA(A) receptor activation. Spontaneous GABAergic postsynaptic currents (PSCs) were recorded in GnRH neurons from OVX+E and OVX mice in coronal and sagittal slices. There were no diurnal changes in PSC frequency in cells from OVX mice in either slice orientation. In OVX+E cells in both orientations, PSC frequency was low during negative feedback but increased at surge onset. During the surge peak, this increase subsided in coronal slices but persisted in sagittal slices. Comparison of PSCs before and during tetrodotoxin (TTX) treatment showed TTX decreased PSC frequency in OVX+E cells in sagittal slices, but not coronal slices. This indicates estradiol acts on multiple GABAergic afferent populations to increase transmission through both activity-dependent and -independent mechanisms. Estradiol also increased PSC amplitude during the surge. Estradiol and the diurnal cycle thus interact to induce shifts in both GABA transmission and postsynaptic response that would produce appropriate changes in GnRH neuron firing activity and hormone release.
    Journal of Neuroscience 03/2007; 27(8):1913-21. · 6.91 Impact Factor
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    Catherine A Christian, Jessica L Mobley, Suzanne M Moenter
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    ABSTRACT: A robust gonadotropin-releasing hormone (GnRH) surge is a prerequisite signal for the luteinizing hormone (LH) surge that triggers ovulation. In rodents, the GnRH surge is initiated by elevated estradiol and a diurnal switch in estrogen action from negative to positive feedback. The ability of constant estradiol treatment to induce daily LH surges was tested in adult mice that were ovariectomized (OVX) or OVX and treated with estradiol implants (OVX+E). LH in OVX mice showed no time-of-day difference. In contrast, OVX+E mice showed a large LH surge (8- to 124-fold relative to the a.m.) in p.m. samples on d 2-5 post-OVX+E. Targeted extracellular recordings were used to examine changes in firing activity of GnRH neurons in brain slices. There was no time-of-day difference in cells from OVX mice. In contrast, OVX+E cells recorded in the p.m. showed an increased mean firing rate and instantaneous firing frequency, which could increase GnRH release, and decreased duration of quiescence between bouts of firing, possibly reflecting increased pulse frequency, compared with cells recorded in the a.m. In the a.m., OVX+E cells showed changes in GnRH neuron firing reflecting negative feedback compared with OVX cells, whereas in the p.m., OVX+E cells exhibited changes suggesting positive feedback. These data indicate that differences in pattern and level of individual GnRH neuron firing may reflect the switch in estradiol action and underlie GnRH surge generation. The persistence of altered GnRH neuron activity in slices indicates that this approach can be used to study the neurobiological mechanisms of surge generation.
    Proceedings of the National Academy of Sciences 11/2005; 102(43):15682-7. · 9.81 Impact Factor