The activation of the gonadotropic axis requires the pulsatile release of the hypothalamic decapeptide GnRH. Reproduction is thwarted in the absence of these pulses. Despite this critical feature of GnRH release, the nature of the central mechanisms that govern this pulsatile release remain unknown. In recent years, Kiss1 neurons of the arcuate nucleus have been posed as likely candidates to hold this pulse generator through the coordinated action of its co-transmitters tachykinin neurokinin B (NKB) and dyrorphin A (Dyn), which has led these neurons to be termed KNDy neurons. I propose a model in which NKB stimulates and Dyn inhibits kisspeptin release from KNDy neurons leading to a pulsatile pattern that would then be translated into GnRH, and therefore LH, pulses. However, we have recently documented that other tachykinins (substance P, SP and neurokinin A, NKA) can activate KNDy neurons, adding an additional complex layer to this model. Importantly, recent studies in rodents and monkeys indicate that the action of tachykinins to induce LH release happens at the level of KNDy neurons and is therefore kisspeptin-dependent. However, we have recently observed that in the presence of circulating estradiol (E2) levels, both NKB and SP evoke a potent increase in LH release in a kisspeptin-independent manner, which compromises the previous model. Importantly, KNDy neurons and GnRH neurons (albeit to a lesser extend) express the receptors for SP (Tacr1) and NKB (Tacr3), suggesting that tachykinins may be able to act at both neuronal levels to induce LH release under the right sex steroid conditions. The overall goal of this proposal is to characterize the role of each tachykinin in the frequency and amplitude of LH pulses in the mouse at the KNDy neuron vs GnRH neuron using a series of complementary functional, neuroanatomical and genetic studies. The successful completion of this proposal will offer new strategies to treat reproductive disorders affecting GnRH secretion.
Reproductive function requires the pulsatile release of the hypothalamic decapeptide GnRH; however, the mechanisms underlying the formation of these pulses remain unknown. While the current thinking considers Kiss1 neurons in the arcuate nucleus (ARC) as GnRH pulse generators through the action of neurokinin B (NKB) and dynorphin, we have recently documented that other tachykinins (neurokinin A, NKA; and substance P, SP) can activate ARC Kiss1 neurons and that NKB and SP can induce LH release in a kisspeptin- independent manner. Therefore, this proposal aims to decipher the role of each tachykinin in the generation of GnRH pulses at the level of the Kiss1 neuron and GnRH neuron. Understanding the mechanisms that govern GnRH pulsatility will increase the number of potential targets to treat reproductive disorders.
| Ross, Rachel A; Leon, Silvia; Madara, Joseph C et al. (2018) PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. Elife 7: |
