Neuroendocrine research of this laboratory utilizes in vivo (rodents) and in vitro (cell lines, primary cultures and organotypic cultures) model systems and post-mortem human brain tissues. Information from studies using anatomical (immunocytochemistry, electron microscopy, in situ hybridization), pharmacological (in vivo drug administration) and molecular approaches (recombinant technologies) are combined to understand (1) the central regulation of the thyroid and adrenal axes and the mechanisms of thyroid hormone actions, further, (2) the central regulation of the hypothalamic-pituitary-gonadal axis and genomic/non-genomic actions of sex steroid hormones in the brain. (1) Research focusing on thyroid regulation and actions includes two major activities: One is to elucidate the pathomechanisms of the non-thyroidal illness syndrome induced by fasting or infection. They investigate the relationship of the hypophysiotropic TRH neurons and the neuronal groups that synthesize feeding-related peptides and neurotransmitters in both the rat and human. Furthermore, they examine the role of these neuronal systems of the basal hypothalamus in the regulation of the HPT axis during fasting and administration of leptin. In studies examining the pathomechanism of the central hypothyroidism induced by infection, they primarily focus on the role of type II deiodinase (D2) synthesized in tanycytes in the regulation of HPT axis and the mechanisms whereby infection induces activation of D2 in this cell type. The second major focus is the study of the molecular regulation of T3 generation in the CNS. Since D2 is the major T3 generating enzyme in the CNS, they focus on the translational and post-translational processing of D2, especially the substrate-induced ubiquitination of D2 along the ERAD pathway and analyze the interacting proteins necessary for this process, such as UBC6 and UBC7. Furthermore, they have studied the role of the short ORFs in the 5 untranslated region of the D2 mRNA in the translation of D2 mRNA. (2) Research in reproductive neuroendocrinology has two major subfields: One is aimed at deciphering receptorial and molecular mechanisms of estrogen actions on the central nervous system, with special respect to the hormonal and neuronal regulation of GnRH neurons during positive and negative estrogen feedback. This research activity extends to the identification of further estrogen-receptive neuronal systems (e.g. distinct chemotypes of GABA-ergic interneurons in the cerebral cortex and the suprachiasmatic nucleus) in rodent and human brains, in vitro studies of estrogen-regulated transcripts in GT1-7 cells and putative presence and functions of extranuclear estrogen receptors in these cells. The most important achievement in this field was the first proof that GnRH neurons are estrogen receptive via ER-beta, a finding currently pursued in the human. The second emerging subfield derives from recent detection of the glutamatergic marker, VGLUT2 in GnRH neurons of the rat. While new collaborations are established and methods including in vitro electrophysiology are introduced to study the role of endogenous glutamate in GnRH cells, the laboratory has also provided proof that endogenous glutamate is a conserved feature in several parvicellular neurosecretory systems (particularly, CRH and TRH neurons) and it also characterizes magnocellular OT and VP neurons. This research activity seeks to attribute a role to endogenous glutamate release from neuroendocrine systems, with special regard to the endogenous pulsatility of neurohormone secretion.