"Mechanisms underlying nicotine induced neuronal toxicity in zebrafish"

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DESCRIPTION (provided by applicant): Embryonic exposure to nicotine has deleterious consequences on human development at various levels. Such exposure can lead to long term changes in the cognitive abilities and behaviors related to learning and memory. Many mammalian models have been employed to understand how nicotine can exert such effects, but this is difficult because most mammalian behaviors and the nervous system underlying them are complex. We are studying the effects of nicotine exposure in a model vertebrate, the zebrafish, with the goal of linking behavioral abnormalities created by nicotine exposure to developmental alterations in spinal neurons and associated spinal musculature. Zebrafish embryos are sensitive to nicotine exposure (Svoboda et. al, 2002). Embryos acutely exposed to nicotine exhibit a swimming-like behavior at time when they typically do not swim. On the other hand, chronically exposing embryos to nicotine, results in paralysis. These two behavioral phenotypes point us toward candidate cell types that may be altered in zebrafish by embryonic nicotine exposure. In this proposal the consequences of embryonic nicotine exposure on spinal neurons and associated musculature will be determined. To our knowledge, this is the first attempt at utilizing the zebrafish model to understand the consequences of embryonic nicotine exposure. The aims are: 1) To systematically identify and characterize all of the zebrafish nAChRs, 2) to determine the consequences of nicotine exposure on motoneuron and muscle development at the mechanistic level, 3) to determine the consequences of nicotine exposure on embryonic sensory neuron development at the mechanistic level, 4) To determine if phenotypes that arise form transient embryonic nicotine exposure persist into adulthood. Each of these aims addresses a fundamental issue relating to how exogenous nicotine potentially exerts its effects during vertebrate development. First, they describe behavioral and neuroanatomical phenotypes that result from early embryonic exposure to nicotine. Secondly, they provide mechanistic insight into how those phenotypes could arise. The work is basic research in developmental neurotoxicology. It serves to establish a foundation whereby zebrafish can be utilized in vivo to unravel the mechanisms that underlie the effects of nicotine exposure during development.