DESCRIPTION: (provided by the applicant) The nervous system regulates the reproductive axis through the activity of the "GnRH pulse generator," neurons in the hypothalamus whose activity governs pulsatile release of gonadotropin-releasing hormone (GnRH). The amplitude and frequency of GnRH pulses are, in turn, regulated by physiological signals, some of which evoke sustained shifts in the activity of the GnRH pulse generator and hence, in overall reproductive state. Metabolic cues, for example, are clearly important for maintenance of GnRH pulsatility in adult animals, and in the deceleration of GnRH pulsatility that occurs under conditions of negative energy balance. Cellular and molecular mechanisms mediating physiological shifts in GnRH pulse generator activity remain unknown. These studies will test the hypothesis that metabolically-linked adjustments of GnRH pulse generator activity are mediated by regulation of ion channels, specifically those known to link cell metabolism to cell excitability - the ATP-sensitive potassium channels (K+ATP channels). The K+ATP channel closes upon binding AlP, leading to reduced cellular K+ permeability, membrane depolarization and thus, increased cell excitability; reduced intracellular ATP produces the opposite conditions, reducing cell excitability. Preliminary work implicates hypothalamic K+ATP channels activity in the modulatation of GnRH release. The proposed studies are therefore designed to determine whether K+ATP channel opening and closing in vivo lead to alterations in GnRH pulse generator activity (Aim 1), assess whether opening of K+ATP channels mediates inhibition of GnRH pulsatility during food-restriction (Aim 2), determine the molecular and functional properties of KATP channels in identified GnRH neurons [Aims 3,4], and determine whether suppression of hypothalamic K+ATP channel expression reverses effects of negative energy balance on GnRH pulsatility (Aim5) A transgenic mouse will also be developed (Aim 6) in which expressesion of overactive (open) K+ATP channel subunits will be targeted to GnRH neurons, permitting examination of the reproductive consequences of K+ATP channel hyperactivity in GnRH neurons. These studies may provide new and important information on cellular mechanisms mediating many major physiological alterations in GnRH pulse generator activity. They may also permit an understanding of how GnRH pulse generation is inhibited in feeding disorders such as anorexia nervosa, or in other hypogonadotropic states, such as functional hypothalamic amenorrhea associated with subclinical eating disorders or rigorous exercise training.
|Effective start/end date||4/1/02 → 3/31/07|
- National Institute of Child Health and Human Development (5 R01 HD020677-17)