Research

The phenomenon underlying episodic GnRH release is often referred to as the "GnRH-pulse generator", which is a nice short way of describing the black box. To understand the pulse generator, we are characterizing basic electrophysiological properties of GnRH and kisspeptin neurons (important upstream inputs to GnRH neurons) and how these change developmentally and throughout the reproductive cycle. We are interested in determining if rhythmicity is an intrinsic property of these cells or if it emerges as a network property, understanding the biophysical events underlying rhythm generation, and studying how GnRH neurons communicate to produce synchronous hormone release. We are also actively studying the role of astroglia as components of the pulse-generating network, and how reproductive state modifies excitation-secretion coupling in GnRH neurons.

Steroid hormones are produced by the gonad in response to GnRH stimulation of pituitary gonadotropin release. Most of the time, steroids provide homeostatic (negative) feedback to regulate GnRH release and pituitary response to GnRH. This is important for maintaining normal fertility in both sexes and cycles in females. Estradiol in females is a special case; it provides homeostatic feedback much of the time but when a mature follicle produces sustained high levels, the action of estradiol switches to positive feedback, inducing a surge of GnRH release that ultimately triggers ovulation.

We are studying the neurobiological mechanisms that underlie this switch using patch-clamp, viral-mediated knock-down of estradiol receptors, and dynamic clamp to study how intrinsic and synaptic changes in GnRH neurons are integrated. We also study how psychosocial stress alters the ability to switch from estradiol negative to positive feedback.

Prenatally androgenized (PNA) female mice exhibit many of the symptoms of hyperandrogenemic polycystic ovary syndrome (PCOS), including early puberty, increased LH levels and GnRH neuron activity, disrupted estrous cycles and increased excitatory input to GnRH neurons in adults. We recently showed neurobiological changes emerge even before mice go through puberty. We are studying the mechanisms underlying these changes and how they change with age and ongoing high androgen levels. We are also collaborating with Shigeki Iwase’s lab in Human Genetics to perform epigenetic analyses of GnRH and kisspeptin neurons through development and how these are altered by PNA treatment. This will allow us to identify how functional changes in the biophysics of GnRH neurons are driven by epigenetic programming. Ultimately, we hope to devise strategies that ameliorate the reproductive phenotypes in PNA female mice, and then translate these to preclinical models and eventually clinical care.