Alcohol exposure in utero can result in Fetal Alcohol Spectrums Disorders (FASD) in the child. Patients with FASD exhibit permanent structural changes in various brain regions, including the hippocampus and functional impairments in many aspects of cognition and behavior. Measures of hippocampal neuroplasticity, including long-term potentiation, synaptic and dendritic organization, and adult neurogenesis, are consistently disrupted in rodent models of FASD. Alterations to these neuroplastic processes contribute to learning and memory deficits observed in individuals with prenatal alcohol exposure. This dissertation examines brain-derived neurotrophic factor (BDNF) as a molecule potentially altered following neonatal alcohol exposure in the rat hippocampus and the neuroimmune response as a potential pathway that exacerbates alcohol-induced damage. BDNF is critical for cell proliferation, maturation, and dendritic outgrowth in the developing and adult brain. Previous work from our lab demonstrated that the number of adult-born dentate gyrus granule cells surviving to maturation is impaired in neonatal alcohol-exposed rats (Klintsova et al., 2007; Hamilton et al., 2012). This dissertation utilizes a third trimester-equivalent (postnatal day [PD] 4-9) binge-like alcohol exposure rat model (AE; 5.25 g/kg/day) with two control groups, sham-intubated (SI) and undisturbed/suckle control (SC). Specific Aim 1 investigated how the brain initially responds to binge-like alcohol exposure by analyzing short-term alterations to expression of BDNF and the neuroimmune response in the hippocampus. Experiment 1 examined protein levels of BDNF and its high-affinity receptor TrkB, Bdnf exon-specific gene expression, and Bdnf DNA methylation in neonatal animals 24 hours following AE (PD10). Experiment 2 analyzed microglial number and activation state, as well gene expression of pro- and anti-inflammatory cytokines on PD10. For Experiment 1, BDNF protein and total gene expression levels were increased in AE animals at PD10, with increases also being found in the sham-intubated animals. Alcohol-specific upregulation of TrkB and Bdnf exon I-specific gene expression was also found. Bdnf exon I DNA methylation was decreased in the AE and SI animals. For Experiment 2, there were fewer microglia in the dentate gyrus and CA1 of AE and SI animals, increased microglia activation in CA1, DG and CA3 specific to the AE group as measured by cell territory, and increased IL-1β, TNF-α, CCL4 and CD11b gene expression in AE and SI animals. CCL4 was even further elevated in AE animals compared to SI. Levels of anti-inflammatory cytokine TGF-β were increased in AE animals compared to SI and SC. This Aim supports investigation of BDNF and TGF-β as neuroprotective responses to alcohol-related insult. Specific Aim 2 examined the long-term effects of neonatal alcohol exposure on BDNF protein and exon-specific gene expression and Bdnf DNA methylation in the hippocampus of adult rats (PD72). In addition, animals were exposed to either a “super-intervention” (WREC; voluntary wheel running (PD30-42) followed by housing in a complex environment (PD42-72)) or continuous wheel running (WRWR; PD30-72). Both interventions have been shown to enhance BDNF and adult neurogenesis (Vivar et al., 2013; Olson et al., 2006; Hamilton et al., 2012). Alterations to basal BDNF protein and gene expression levels were transient as AE animals do not differ from controls on PD72 in standard housing. Rats housed in WRWR, but not WREC, show higher levels of hippocampal BDNF protein and gene expression. Steady-state Bdnf exon I methylation was not altered by neonatal condition, however, WRWR was associated with less methylation in control animals. Specific Aim 3 investigated whether AE affects hippocampal adult neurogenesis and dendritic morphology in adult (PD72) male rats and whether exposure to either WREC or WRWR impacts these measures. As expected, AE did not affect cell proliferation or number of immature neurons, but significantly decreased dendritic complexity of the immature neurons compared to SI and SC groups. Specifically, there were significant decreases in dendritic material, number of intersections, and number of bifurcations per radius. WREC and WRWR both robustly enhanced dendritic complexity in the AE animals, and while WRWR modestly increased complexity in SI and SC animals and WREC had little effect. Specific Aims 3 demonstrates the long-lasting impact of neonatal alcohol exposure on dendritic morphology of immature neurons in the hippocampus, which could contribute to alcohol-related deficits in granule cell survival observed in this model. These studies also support the implementation of exercise and complex environments as therapeutic interventions for individuals with FASD.
|Adviser||Anna Y. Klintsova|
|School||UNIVERSITY OF DELAWARE|
|Subjects||Neurosciences; Psychobiology; Behavioral psychology; Cognitive psychology|
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