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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA015413-01A1
Application #
6973716
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Sorensen, Roger
Project Start
2005-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$218,500
Indirect Cost
Name
Upstate Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
Middleton, Frank A; Varlinskaya, Elena I; Mooney, Sandra M (2012) Molecular substrates of social avoidance seen following prenatal ethanol exposure and its reversal by social enrichment. Dev Neurosci 34:115-28
Mooney, S M; Miller, M W (2011) Role of neurotrophins on postnatal neurogenesis in the thalamus: prenatal exposure to ethanol. Neuroscience 179:256-66
Mooney, Sandra M; Miller, Michael W (2010) Prenatal exposure to ethanol affects postnatal neurogenesis in thalamus. Exp Neurol 223:566-73
Mooney, Sandra M; Miller, Michael W (2009) Vulnerability of macaque cranial nerve neurons to ethanol is time- and site-dependent. Alcohol 43:323-31
Mooney, S M; Miller, M W (2007) Nerve growth factor neuroprotection of ethanol-induced neuronal death in rat cerebral cortex is age dependent. Neuroscience 149:372-81
Mooney, Sandra M; Miller, Michael W (2007) Time-specific effects of ethanol exposure on cranial nerve nuclei: gastrulation and neuronogenesis. Exp Neurol 205:56-63
Mooney, Sandra M; Miller, Michael W (2007) Postnatal generation of neurons in the ventrobasal nucleus of the rat thalamus. J Neurosci 27:5023-32
Miller, Michael W; Mooney, Sandra M; Middleton, Frank A (2006) Transforming growth factor beta1 and ethanol affect transcription and translation of genes and proteins for cell adhesion molecules in B104 neuroblastoma cells. J Neurochem 97:1182-90