Regulation of learning and memory by steroid hormone signaling during development and aging

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.

Grant Number: 5R01AG068194-03
NIH Institute/Center: NIH
Principal Investigator: Kaveh Ashrafi