OHSU researchers reveal mechanism of neuronal activity that controls fertility

Reproductive function is a highly regulated process that depends on certain hormones interacting in a controlled and rhythmic manner.  The hypothalamus and pituitary together control pubertal development and fertility; the hypothalamus releases a chemical messenger called gonadotropin-releasing hormone, which attaches to specific receptors of the pituitary gland, in turn releasing reproductive hormones that control ovulation in females and sperm production in males.

In females, the hypothalamus releases GnRH in appropriately timed pulses and in one massive release, or “surge”, of GnRH to trigger ovulation. Sets of neurons in the hypothalamus that produce a protein called kisspeptin play an essential role in this process. One population resides in an area called the arcuate nucleus and the other in the preoptic nucleus. Recent studies suggest the arcuate nucleus is responsible for triggering the rhythmic release of GnRH, whereas the preoptic nucleus induces the surge of GnRH. However, the mechanics of how this is achieved in each brain region remained unclear.

Using a technique called optogenetics, researchers from OHSU and the University of Washington explored whether kisspeptin-producing neurons in the arcuate nucleus are able to communicate with each other to drive pulses of GnRH ion mice.  The team genetically modified the mice to express a light-sensitive ion channel protein in their kisspeptin neurons, allowing them to activate these neurons with beams of light. As predicted, this caused kisspeptin neurons throughout the arcuate nucleus to coordinate their activity. Stimulation of the arcuate nucleus also triggered release of excitatory and inhibitory peptides, which synchronized the firing of the neurons. These findings provide a cellular model for previous findings that correlated burst firing activity of arcuate nucleus neurons with serum LH pulses in several species including nonhuman primates.

The light-induced stimulation also triggered the release of the neurotransmitter, glutamate, which caused kisspeptin neurons within the preoptic nucleus to fire in bursts. This in turn excited the GnRH neurons. Together, these findings show that kisspeptin neurons in both areas of the brain coordinate their activity to stimulate the release of GnRH from the hypothalamus, consequently controlling fertility. A future challenge is to investigate in living animals whether the cellular model translates into pulses of GnRH and LH, and that activation of arcuate kisspeptin neurons participate in the generation of the GnRH and LH surge. Therefore, these results set the stage for further exploration of the kisspeptin-GnRH neuronal circuits, and to obtain insights into the role of neuronal peptide signaling in healthy as well as diseased states.

High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons,” was published on Aug 23, 2016 in the journal eLIFE. OHSU’s Jian Qiu, Ph.D., research assistant professor in the Department of Physiology & Pharmacology, and Casey C. Nestor, Ph.D., joint postdoctoral researcher in the Kelly/Rønnekleiv Labs, are co-first authors  on the paper. Martin J. Kelly, Ph.D. and Oline K. Rønnekleiv, Ph.D. are joint senior authors. Other contributors are Chunguang Zhang, Ph.D. a senior research associate in the Rønnekleiv/Kelly labs, and Stephanie L. Padilla, Ph.D. and Richard D. Palmiter, Ph.D. from the Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle.

This research was mainly funded by National Institute of Health (NIH) grants R01-NS38809 (MJK), R01-NS43330 (OKR), R01-DK68098 (MJK and OKR) and F32 DK104366 (CCN).