Functional characterization of neural circuits controling puberty in female mice
Final Report Abstract
Puberty is a transition period of reproductive development from juvenile stages to adulthood and depends upon activity of gonadotropin-releasing hormone (GnRH) neurons. GnRH neurons are initially activated in utero, but remain quiescent throughout the juvenile period. Premature reactivation of GnRH neurons results in precocious puberty in mice and humans, but the mechanisms underlying developmental control of GnRH neuron activity remain unknown. The neuropeptide kisspeptin, a potent activator of GnRH neurons that is implicated as a critical permissive signal triggering puberty and a major regulator of the adult female hypothalamus-pituitary-gonadal (hpg) axis, is paradoxically produced by neurons in the developing brain well before puberty onset. Thus the neural circuits controlling the timing of reproductive maturation remain elusive. We have delineated the underlying neural circuitry using conditional genetic transsynaptic tracing in female mouse embryos. We find that kisspeptinproducing neurons in the arcuate nucleus (ARC) already communicate with a specific subset of GnRH neurons in utero. We show that ARC kisspeptin neurons are upstream of GnRH neurons and that GnRH neuron connectivity to ARC kisspeptin neurons does not depend on their spatial position in the brain. Furthermore, we demonstrate that the neural circuits between ARC kisspeptin and GnRH neurons are fully established and operative before birth. Finally we find that most GnRH neurons express the kisspeptin receptor GPR54 upon circuit formation, suggesting that the signaling system implicated in gatekeeping puberty becomes operative in the embryo. Distinct roles have been proposed for AVPV and ARC kisspeptin neurons during reproductive maturation and in mediating estrogen feedback on the hpg axis in adult females. Despite their pivotal role in the regulation of reproductive physiology, little is known about kisspeptin neuron connectivity in adult female mice. While previous data suggest heterogeneity within the AVPV and ARC kisspeptin neuron populations, how many and which of these potential kisspeptin neuron subpopulations are actually communicating with GnRH neurons was not known. We analyzed the connectivity of individual kisspeptin neurons with the GnRH neuron population in female mice with a single cell resolution using a combinatorial genetic transsynaptic tracing strategy. We find that only subsets of AVPV and ARC kisspeptin neurons are synaptically connected with GnRH neurons. We demonstrate that the majority of kisspeptin neurons within the AVPV and ARC does not communicate with GnRH neurons. Furthermore, we show that all kisspeptin neurons within the AVPV connected to GnRH neurons are estrogen-sensitive and that most of these express tyrosine hydroxylase. Our data demonstrate functional specialization within the two kisspeptin neuron populations.
Publications
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(2013). Genetic dissection of puberty in mice. Exp Physiol 98:1528-1534
Kumar D & Boehm U
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(2014). Conditional genetic transsynaptic tracing in the embryonic mouse brain. J Vis Exp 94:e52487
Kumar D & Boehm U
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(2014). Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero. J Neurosci 34:3756- 3766
Kumar D, Freese M, Drexler D, Hermans-Borgmeyer I, Marquardt A, Boehm U
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(2015) In utero development of kisspeptin/GnRH neural circuitry in male mice. Endocrinology 156:3084-3090
Kumar D, Periasamy V, Freese M, Voigt A, Boehm U
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(2015). Specialized subpopulations of kisspeptin neurons communicate with GnRH neurons in female mice. Endocrinology 156:32-38
Kumar D, Candlish M, Periasamy V, Avcu N, Mayer C, Boehm U
