The long-term objective of this project is to identify cellular mechanisms underlying ethanol-induced changes in neuronal development, and to assess the role of these changes in the etiology of CMS abnormalities that characterize alcohol-related neurodevelopmental disorders (ARND) and fetal alcohol syndrome (FAS). Neuropathologic features of ethanol exposure during development include altered postmitotic neuron morphogenesis in the hippocampus and abnormal intrahippocampal circuitry, which are thought to contribute to visuospatial and memory deficits. Our previous findings suggest that ethanol disrupts the timing of initial outgrowth and subsequent growth dynamics of hippocampal pyramidal neuron axons in vitro and reorganizes the microtubule and actin cytoskeletons in their growth cones. This project tests hypotheses regarding the cellular mechanisms underlying these effects in low-density fetal rat hippocampal pyramidal neuron cultures using molecular and pharmcologic approaches and high temporal resolution phase contrast and confocal imaging of live cells. Experiments are designed to determine whether ethanol-induced changes in neuronal process outgrowth involves altered signaling through small Rho-family GTPases and/or modulation of calcium signaling, including spontaneous, growth-regulating calcium transients in the growth cone. In vivo experiments will describe ethanol's morphoregulatory effects on axons and their dendritic targets in the developing rat hippocampus, in which the spatiotemporal expression of extracellular growth- regulating signals are retained. Results will establish whether altered signaling pathways regulating axonal and dendritic growth are a key aspect of ethanol's neurodevelopmental effects and will test an animal model for future verification of these effects in vivo. This work will reveal cellular mechanisms of ethanol-induced neuronal damage that may serve as targets for new therapeutic strategies to prevent or treat ARND and FAS.
| Lindsley, Tara A; Mazurkiewicz, Joseph E (2013) Ethanol modulates spontaneous calcium waves in axonal growth cones in vitro. Brain Sci 3:615-26 |
| Pearson, Yanthe E; Castronovo, Emilio; Lindsley, Tara A et al. (2011) Mathematical modeling of axonal formation part I: Geometry. Bull Math Biol 73:2837-64 |
| Mah, S J; Fleck, M W; Lindsley, T A (2011) Ethanol alters calcium signaling in axonal growth cones. Neuroscience 189:384-96 |
| Lindsley, Tara A; Shah, Samit N; Ruggiero, Elizabeth A (2011) Ethanol alters BDNF-induced Rho GTPase activation in axonal growth cones. Alcohol Clin Exp Res 35:1321-30 |
| Kerlin, Aaron M; Lindsley, Tara A (2008) NeuroRhythmics: software for analyzing time-series measurements of saltatory movements in neuronal processes. J Neurosci Methods 173:147-52 |
| Lindsley, Tara A; Kerlin, Aaron M; Rising, Lisa J (2003) Time-lapse analysis of ethanol's effects on axon growth in vitro. Brain Res Dev Brain Res 147:191-9 |
| Yanni, Penelope A; Rising, Lisa J; Ingraham, Christine A et al. (2002) Astrocyte-derived factors modulate the inhibitory effect of ethanol on dendritic development. Glia 38:292-302 |
