The controlled addition of fluoride into public water supplies reduces the prevalence of dental disease and has been a cost effective way to deliver fluoride to the community. However, some speculate that fluoride at high levels may be toxic to several physiological systems including the nervous system. In the proposed studies, we will investigate whether ingested fluoride, at physiological levels, causes neurobehavioral effects in mice. Our preliminary studies found that fluoride induced behavioral changes in female A/J mice given 50 ppm fluoride in their drinking water for at least 3 weeks. We will examine the effects of gender, dose and genetic background in the neurobehavioral effects of fluoride. Our specific aims are: 1) To characterize the neurobehavioral responses to fluoride in inbred mice with different susceptibilities to dental fluorosis, and 2) To determine whether fluoride exposure affects learning and memory in mice. Two strains of mice, A/J (enamel fluorosis sensitive), and C57BL/6 (normal fluoride response), including both males and females, will be exposed to different levels of fluoride in drinking water and then analyzed for fluoride-related alterations in behavior. These behavioral tests will investigate sensorimotor deficits, anxiety, locomotion, and hyperexcitability. Brain and serum fluoride levels will be determined, and molecular markers known to be associated with learning and memory will be compared in fluoride treated and control mice. The proposed studies cross over several disciplines and will be addressed by a collaborative effort between the Gladstone Neurological Institute and UCSF School of Dentistry. The broad scientific and collaborative strengths of both institutions will ensure the careful completion of all aspects of these studies. Findings from these experiments will deepen our understanding of fluoride toxicity and will help to direct future human studies in the important goal to continue to assess relative risk/benefit rations of fluoride in specific populations. PUBLIC HEALTH RELEVANCE: Fluoride is important for optimal dental health. However, at higher fluoride concentrations, animal and human studies have suggested neurological effects of fluoride that have been linked to behavioral changes. In this application we will expose mice to fluoride in drinking water that results in physiologically relevant serum fluoride concentrations, to determine the effects of fluoride on behavior relative to dose, sex, and strain of mouse.