The central hypothesis of this proposal is that suppression of GnRH/LH secretion during lactation is due to suckling- induced alterations in hypothalamic neural systems that regulate food intake and energy balance. Lactation is characterized by an excessive hyperphagia and negative energy balance due to milk production. Our studies have established that several hypothalamic neuropeptide orexigenic systems involved in regulating food intake/energy balance (NPY, orexin, melanin concentrating hormone [MCH], neurokinin B [NKB}) make direct connections with GnRH neurons, thus providing a neuroanatomical framework by which signals denoting changes in food intake/energy balance can be directly transmitted to GnRH neurons. The proposed studies will use a multidisciplinary approach to explore the following basic questions: 1) Do orexigenic and anorexigenic neuropeptides directly modulate GnRH neuronal activity and exert an increased inhibitory tone during lactation? Studies will use hypothalamic explants and electrophysiology to determine if agonists and antagonists to NPY, orexin, MCH or NKB receptors have direct effects on GnRH neurons. 2) Is the lactation-specific induction of NPY in the dorsomedial hypothalamic nucleus involved in the suppression of GnRH activity? Studies will examine the functional role of the suckling-specific induction of NPY in the suppression of GnRH/LH. 3) Are the profound suppression of leptin and the hypoinsulinemia associated with lactation important permissive signals that allow arcuate nucleus neurons to drive the suppression of GnRH neuronal activity and hyperphagia? Studies will restore leptin and insulin to postlactation levels and determine effects on hypothalamic neuropeptide feeding systems and on restoration of GnRH/LH secretion. Subsequent experiments will use ablation techniques to determine the functional relevance of identified factors in the suppression of GnRH neuronal activity during lactation. The lactating rat provides a physiological model for studying a number of conditions in women (undernutrition, anorexia nervosa, bulimia, exercise-induced amenorrhea and lactation) that involve a suppression of reproductive function associated with negative energy balance. The lactating rat is also a model of chronic hyperphagia and provides the opportunity to study physiological mechanisms underlying conditions of greatly increased food intake and may provide insights into causes of obesity. ? ? ?
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