PROJECT SUMMARY/ABSTRACT There is currently a paucity of therapeutic approaches for ameliorating cognitive declines that characterize neurodegenerative disorders such as Alzheimer's Disease (AD) and AD related dementias (ADRDs). Defects in learning and memory also accompany 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 accompanies human aging and neurodegenerative disorders including AD and ADRDs. Using genetic manipulations, we previously showed that reducing KYNA levels substantially improves learning and memory in aged C. elegans as well as in C. elegans models of neurodegeneration. 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. We have identified androst-5-ene-3β,17β-diol (ADIOL), a C19 steroid hormone, as a potent reducer of KYNA and enhancer of learning capacity in C. elegans. We have demonstrated that the effects of ADIOL are dependent on an NHR-91, a transcription factor with both sequence and functional homology to mammalian estrogen receptor β, ERβ. These findings are intriguing for two key reasons: (i) The existence of ADIOL has long been recognized in mammals but the physiological functions of this steroid hormone are extremely poorly understood, (ii) There is compelling evidence that activation of ERβ in mammals has numerous beneficial effects including improved learning and memory but the underlying mechanisms are unknown. We hypothesize that ADIOL serves as an endogenous ligand to activate an ERβ-like nuclear hormone receptor, which in turn causes reductions in KYNA to promote learning and memory. Our specific aims are to rigorously establish the role of ADIOL in learning and memory during aging and in C. elegans models of neurodegeneration, devise biochemical strategies for quantitating this steroid hormone from C. elegans, investigate the role of nhr-91 as a mechanistic link between ADIOL and KYNA, and explore three hypotheses pertaining to the physiological roles of ADIOL including its role in aging, as a mechanism that links nutrient sensory pathways to learning and memory via KYNA, and as a mechanism that links development of reproductive capacity to mechanisms of learning and memory. This investigation employs C. elegans molecular genetics, imaging, behavioral assays, as well as biochemical measurements of metabolites.