The overall objectives of this project are to ascertain the mechanisms by which 17 beta-estradiol (E2) regulates GnRH neuronal excitability. GnRH neurons are crucial for the survival of the species, and both E2 and neurotransmitters are critical for the neurosecretory properties of these neurons. However, only limited knowledge is available on the cellular mechanisms by which GnRH neurons are regulated. The recent development of transgenic mice with green fluorescent protein (EGFP)-tagged GnRH neurons has greatly facilitated studies of these important neurons. Recent evidence suggests that E2 through ERbeta acts directly on GnRH neurons, as well as indirectly through ERalpha on GABA neurons to affect GnRH production and/or release. In addition, E2 alters the potency of neurotransmitters that may directly or indirectly affect GnRH neurons. Despite this growing appreciation, E2 regulation of GnRH neurons is incompletely understood. To further explore the distinct electrical properties of GnRH neurons that govern GnRH excitability and how E2 modulates these properties, we will focus on selective ion channels and receptors based on a model for burst firing in GnRH neurons. Our working hypothesis is that E2 modulates synaptic input and ion channel function acutely through membrane signaling events and over a longer time period alters the expression of specific receptors and ion channels in GnRH neurons. These changes will enhance or inhibit GnRH neuronal activity and GnRH release depending on the steroid mileu of the female, which ultimately regulates fertility.
Our Specific Aims focus on key issues regulating GnRH neurons during positive feedback of LH (GnRH) secretion: (1) To measure the mRNA expression of ATP-sensitive potassium channel subunits, and determine whether E2 alters this expression. (2) To measure the acute effects of E2 on K-ATP channel function, and determine the cellular mechanism(s). (3) To ascertain whether E2 increases alpha1-adrenergic receptor mRNA expression and protein. (4) To measure the effects of E2 on the alpha1-adrenergic inhibition of a small conductance calcium-activated K+ (SK) current that underlies the medium afterhyperpolarization. (5) To ascertain whether E2 increases the mRNA expression of calcium T-channel subunits, and increases T-channel activity leading to enhanced burst firing. These studies will provide new and important information on how estrogen alters intrinsic conductances of hypothalamic GnRH neurons and how estrogen in general modifies synaptic input and thereby facilitates distinct firing patterns in GnRH neurons, which is critical for reproductive competence.
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|Qiu, Jian; Bosch, Martha A; Meza, Cecilia et al. (2018) Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance. Endocrinology 159:647-664|
|Rivera, H M; Stincic, T L (2018) Estradiol and the control of feeding behavior. Steroids 133:44-52|
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|Kelly, Martin J; Qiu, Jian; Rønnekleiv, Oline K (2018) TRPCing around the hypothalamus. Front Neuroendocrinol 51:116-124|
|Padilla, Stephanie L; Qiu, Jian; Nestor, Casey C et al. (2017) AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc Natl Acad Sci U S A 114:2413-2418|
|Heppner, Kristy M; Baquero, Arian F; Bennett, Camdin M et al. (2017) GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance. eNeuro 4:|
|Qiu, Jian; Nestor, Casey C; Zhang, Chunguang et al. (2016) High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. Elife 5:|
|Zhang, Chunguang; Bosch, Martha A; Qiu, Jian et al. (2015) 17?-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice. Mol Endocrinol 29:518-27|
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