Function and Organization of Gonadotropin-Releasing Hormone Neuronal Circuitry

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and is characterized by irregular menstrual cycles and elevated androgens. The central neuronal system that regulates downstream reproductive function communicates through gonadotropin-releasing hormone (GnRH) neurons. Shifts in GnRH pulse frequency during the normal menstrual cycle signal the pituitary to release hormones that regulate follicular maturation and ovarian steroid production. Hormonal feedback is conveyed to GnRH neurons through their afferent network, however the circuitry and activity of this network is not well understood. In most adult women with PCOS this neuronal system is persistently overactive leading to failure of ovulation and high androgen production. When this increased neuroendocrine activity begins is not known, however neuronal hyperactivity during development could result in altered network connectivity and function in adulthood. Exposure to elevated androgens during development results in phenotypes that are similar to PCOS in many species. Our hypothesis is that GnRH neuron activity during the prepubertal period is critical for attracting appropriate synaptic inputs and that prenatal androgenization (PNA) alters this activity and synaptogenesis and thus the adult connectivity and function of the GnRH neuronal circuitry. To test this hypothesis we will study how PNA alters the adult organization of the GnRH neuronal network and the function of afferent inputs to GnRH neurons during prepubertal development. In Aim 1 we will test the hypothesis that PNA increases the frequency and amplitude of GABAergic and glutamatergic postsynaptic currents (PSCs) to prepubertal GnRH neurons and that this occurs through an increased density of synaptic connections. Whole-cell electrophysiological recordings of PSCs will be made to examine the spontaneous function of these inputs during prepubertal development. Evoked activity will be used to identify synaptic connections that have been established but are not yet active. In Aim 2 we will test the hypothesis that developmental exposure to elevated androgens results in altered adult organization of the presynaptic network to GnRH neurons in females. We will utilize a viral tracer targeted to Cre recombinase-expressing GnRH neurons to map the circuitry of the GnRH neuronal network in combination with immunofluorescence and/or in situ hybridization to identify neuron phenotype. This will allow us to characterize the number, location and identify of GnRH neuron afferents and to examine if this connectivity is altered by developmental exposure to androgens. Both Aims will further our knowledge of typical GnRH neuron development beyond the study of individual neurons to comprehension of network interactions with great potential to address long-standing questions about hypothalamic regulation of fertility. They will also further our understanding of how PNA alters the GnRH neuronal network. The broad implications and intellectual depth of this project are essential elements for my training as a physician-scientist.