Controle neuroendócrino da reprodução: fatores que modulam a atividade de neurônios GNRH e kisspetina.

Abstract

GnRH neurons and kisspeptin neurons represent the two neuronal populations of major importance in the control of the reproduction. Sexual steroids have an essential role in the modulation of GnRH neuron network. During the female reproductive cycle, estradiol binds to its receptor expressed by kisspeptin neurons and, exerts both negative and positive feedback at both the central level to alter GnRH release. Many studies of the neurobiological mechanisms underlying estradiol feedback have been done on ovariectomized, estradiol-replaced (OVX+E) mice. In this model, GnRH neuron activity depends on estradiol and time of day, and the activity increase in the late afternoon coincident with a daily LH surge. Amplitude of this surge appears lower than in proestrous mice, perhaps because other ovarian factors are not replaced. We hypothesized GnRH neuron activity is greater during the proestrous-preovulatory surge than the estradiol-induced surge. Our results demonstrated that although the overall GnRH neuron firing rate was similarly between proestrus and OVX+E mice, the patterning of action potentials revealed a shift towards longer burst duration in proestrous mice, whereas intervals between spikes were shorter in OVX+E mice. LH response to an early afternoon injection of GnRH was greater in proestrous than diestrous or OVX+E mice. These observations suggest the lower LH surge amplitude observed in the OVX+E model is likely not attributable to altered mean GnRH neuron activity, but due to reduced pituitary sensitivity, subtle shifts in action potential pattern, and/or excitation-secretion coupling in GnRH neurons. Prolactin is another hormone with impact in the modulation of the HPG axis. Previous studies have shown that kisspeptin neurons are important mediators of prolactin's effects on reproduction. However, the cellular mechanisms recruited by prolactin to affect kisspeptin neurons remain unknown. We observed that a small percentage of kisspeptin neurons in the AVPV nucleus was indirectly depolarized by prolactin. This effect required the PI3K signaling pathway. No effects on the activity of ARH kisspeptin neurons were observed, despite a high percentage of arcuate neurons expressing prolactin-induced STAT5 phosphorylation. Additionally, mice carrying Stat5a/b inactivation in kisspeptin cells were generated. These mutants exhibited an early onset of estrous cyclicity, indicating that STAT5 transcription factors exert an inhibitory effect on the timing of puberty. This study was important to describe new insight about the neurons involved in the control of reproduction.