Early exposure to ethanol profoundly affects development of the nervous system. Indeed, fetal alcohol exposure has been described as the primary cause of mental retardation. During development, neurons are overproduced and a subset are eliminated during a period of naturally occurring neuronal death (NQND). NOND is the mechanism used to match projection and target populations within a system Exposure to ethanol interferes with numerical matching in the trigeminal-somatosensory (tri-ss) system. There are 33% fewer neurons in the principal sensory nucleus of the trigeminal nerve and somatosensory cortex (2nd and 4th order neurons) in ethanol-treated rats. In contrast, the number of neurons; n the thalamic ventrobasal nucleus (VB) (3rd order neurons) is not altered by ethanol. Neuronal survival results from the ability of young neurons to successfully compete for neurotrophin(s) (e.g., nerve growth factor; that are available in limited supply. Expression and activity of these factors is compromised by ethanol. The proposed project will test the hypothesis that ethanol-induced disruption of neurotrophin systems underlies the changes in the tri-ss organization. Two complementary studies will be performed. (1) In vivo experiments will examine the effect of ethanol on neurotrophin ligand and receptor expression in both the somatosensory cortex and the VB. The possibility that ethanol targets an autrocine/paracrine -regulation will be explored with a combined immunohistochemical-in situ hybridization approach. (2) In vitro studies will examine the effects of ethanol on expression and activation of neurotrophin receptors, and activation of signaling pathways. Studies will use organotypic slice cultures that maintain the thalamocortical afferents that can retrogradely transport neurotrophins from cortex to thalamus. These studies will (1) assess mechanisms by which ethanol disrupts tri-ss development, (2) provide valuable data on neurotrophin function, and (3) be a base for future mechanistic studies of the role of neurotrophins in development.
