PROJECT SUMMARY/ABSTRACT There is currently a paucity of therapeutic approaches for ameliorating cognitive declines that characterize neurodegeneration and aging. We have been investigating kynurenic acid, KYNA, a tryptophan derived metabolite, as a nexus in metabolism, aging, and learning and memory in C. elegans. There is compelling evidence from multiple species including C. elegans and mice that reductions in KYNA improve learning and memory while increases in this neuromodulatory metabolite have detrimental effects. In both C. elegans and mice KYNA accumulates with age. KYNA accumulation also characterizes several forms of human neurodegeneration. We previously demonstrated that KYNA reducing genetic manipulations substantially improve learning and memory even in aged animals or those with learning deficits. These improvements are due to specific effects of KYNA on the activity of neurons that express N-methyl D-aspartate receptors (NMDARs), fundamental regulators of learning and memory across phylogeny. These findings prompted us to seek molecular mechanisms and pharmacological reagents for reducing KYNA to improve learning and memory. We have identified androst-5-ene-3β,17β-diol (ADIOL), a C19 steroid hormone, as a potent enhancer of learning capacity in C. elegans. We have demonstrated that ADIOL promotes learning in a KYNA and NMDAR-dependent manner and that the effects of ADIOL are dependent on a nhr-91, a transcription factor with both sequence and functional homology to mammalian estrogen receptor b, ER b. These findings are intriguing for several reasons: first, the existence of ADIOL has long been recognized in mammals but the physiological functions of this steroid hormone are extremely poorly understood. Second, there is compelling evidence that activation of estrogen receptor b in mammals has numerous beneficial effects including on enhancements of learning and memory but the underlying mechanisms for these effects are unknown. We hypothesize that ADIOL serves as an endogenous ligand to activate an ER b-like nuclear hormone receptor, which in turn causes reductions in KYNA to promote learning. Our objectives are to understand the molecular mechanisms through which ADIOL treatment causes KYNA reduction as well as the physiological roles of ADIOL. Our specific aims are to rigorously establish the role of ADIOL in learning and memory, devise biochemical strategies for quantitating this difficult to measure steroid hormone from C. elegans, investigate the role of nhr-91 as a mechanistic link between ADIOL and KYNA, and explore the hypothesis the physiological roles of ADIOL include linking reproductive capacity and/or nutritional status to neural mechanism of learning and memory. This investigation employs C. elegans molecular genetics, imaging, behavioral assays, as well as biochemical measurements of metabolites.