Biomedical Sciences ETDs

Publication Date

7-1-2014

Abstract

Alcohol is a potent teratogen to the developing CNS, and moderate-heavy alcohol intake during pregnancy causes fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD). These patients display CNS symptoms associated with developmental deficits, cognitive impairment and social abnormalities, with structural impairments in several brain regions. In this dissertation, we investigated the role of FASD in neurogenic functional deficits in the adult hippocampal dentate gyrus. The dentate gyrus is a subregion of the hippocampus that displays unique plasticity, in that new dentate granule neurons are continuously produced throughout life. Adult hippocampal neurogenesis is thought to play key roles in pattern separation and associative learning and in depression-like behaviors. Interestingly, adult neurogenesis is stimulated by physical and social enrichment (enriched environments) and learning. It is becoming increasingly apparent that prenatal alcohol exposure produces long-lasting impairments in postnatal hippocampal neurogenesis and learning impairment. My dissertation research addressed the hypothesis that prenatal alcohol exposure (FASD) impairs the EE-mediated survival and electrophysiological properties of newborn DGCs in the adult hippocampus. Utilizing a combination of histological, behavioral and electrophysiological approaches, we addressed the following specific aims Specific Aim 1: To determine whether prenatal alcohol (FASD) impairs the neurogenic response to environmental enrichment in adult Nestin:CreERT2:YFP bitransgenic mice; and if so, to delineate the stage of neural stem cell lineage most impacted by prenatal alcohol exposure. Specific Aim 2: To determine whether adult-generated DGCs in FASD mice display normal electrophysiological properties after developing under standard and enriched conditions. Specific Aim 3: To determine whether adult-generated DGCs in FASD mice display dendritic morphological plasticity in response to enriched environment. My overall findings indicate that FASD severely impairs the late-stage survival of adult-generated DGCs and disrupts the electrophysiological response to EE in the existing granule cell layer, and that this is accompanied by heightened excitatory synaptic transmission in surviving DGCs. These findings suggest that FASD imparts resistance to the full benefits of social and physical enrichment therapies through both impairment of neurogenic and GCL circuitry mechanisms.

Keywords

Adult hippocamapal neurogenesis, Fetal alcohol spectrum disorder, prenatal alcohol exposure

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Fernando, Valenzuela

Second Committee Member

Andrea, Allan

Third Committee Member

Michael, Wilson

Fourth Committee Member

Helen, Hathaway

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