PROJECT SUMMARY Cadmium (Cd) is a heavy metal of high interest to the Superfund Initiative. It has no known physiological function but is a neurotoxicant. Cd exposure is associated with cognitive and olfactory impairment in humans. However, little is known concerning the underlying molecular and cellular mechanisms. This grant explores the molecular and cellular basis for the deleterious effects of Cd on olfaction and cognition in mouse models, with a focus on its effects on adult neurogenesis and Ca2+signaling critical for hippocampus-dependent memory. We hypothesize that Cd interferes with adult neurogenesis in the dentate gyrus of the hippocampus and in olfactory bulb, and disrupts Ca2+signaling in neurons. We further hypothesize that these adverse cellular and molecular effects may underlie Cd neurotoxicity in cognition and olfaction. We will test these hypotheses both in primary cultured neural stem cells and in vivo in mice. Studies proposed here will provide new insights concerning mechanisms of Cd neurotoxicity, establish animal models to ascertain a causal relationship between Cd exposure and impairment in cognition and olfaction, and elucidate underlying cellular and molecular mechanisms. The proposed studies may provide useful information for Cd risk assessment and designing prevention and intervention strategies against Cd -induced neurotoxicity.