Functional characterization of neural circuits controling puberty in female mice

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Puberty onset is initiated in the brain by activating gonadotropin-releasing hormone (GnRH) neurosecretion. Different permissive signals must be integrated for the initiation of reproductive maturation, however the neural circuits controlling timely awakening of the reproductive axis are not understood. The identification of the neuropeptide kisspeptin as a potent activator of GnRH neuronal activity has provided an opportunity for understanding how timing and progression of puberty are controlled. We have recently shown that two estrogen receptor α -dependent mechanisms – one acting like a “brake” and the other acting like an “accelerator” - are sequentially operated in kisspeptin-producing neurons during pubertal development of female mice to gate, and then to activate GnRH release. Our data suggest that the temporal coordination of juvenile restraint and subsequent pubertal activation are mediated by two separate neural circuits in the hypothalamus. We hypothesize that kisspeptin neurons in the arcuate nucleus (ARC) control puberty onset whereas kisspeptin neurons in the anteroventral periventricular nucleus (AVPe) control completion of puberty. The aim of this proposal is to test this hypothesis and analyze the functional role of ARC and AVPe neural circuits during puberty. We will analyze the neural circuitry of ARC and AVPe kisspeptin neurons using a genetic transneuronal tracing approach. Also we will investigate these circuits in living animals using optogenetic activation/inhibition of ARC and AVPe kisspeptin neurons, respectively, while monitoring the animal's endocrine state.