The brain damage resulting from excessive alcohol exposure may itself contribute to the self-perpetuating nature of human alcoholism. Our goals for this translational research project are twofold: 1) to demonstrate alcohol-induced brain damage in the rat when animals are exposed to high levels of alcohol and scheduled withdrawals and 2) to determine whether rats, selectively bred to drink high amounts of alcohol, drink in a pattern or quantity insufficient to produce neurotoxicity or, alternatively, have also inadvertently been selected for resistance to alcohol neurotoxicity. In the previous INIA funding cycle we found that substantial voluntary drinking by the P rat was only modestly neurotoxic as demonstrated with magnetic resonance (MR) imaging. MR-detectable brain abnormalities were limited to attenuated growth of the corpus callosum, with suggestion of effect in the hippocampus and cerebellum. We now propose to use the alcohol vapor chamber method to increase exposure and to schedule withdrawals, which we predict will enhance alcohol-induced brain damage, detectable with in vivo structural MRI of the whole brain and 2D J-resolved MR spectroscopyof ventromedial subcallosal gray matter. Hypothesis-guided postmortem histological and exploratory gene expression studies will confirm and extend in vivo observations.
Specific Aims 1 -3 will use two alcohol- preferring/non-preferring rat strains and their selection stock: P, NP, Wistar (W) and HAD-1, LAD-1, N/NIH rats. Our MR developments and expertise will be provided to other investigators through Specific Aim 4.
Aim 1 : Use in vivo MR to demonstrate structural and brain metabolite abnormalities in P and HAD-1 rats after vapor chamber exposure to and withdrawals from high levels of alcohol starting in peri-adolescence. Hypothesis: Alcohol treatment will result in attenuated growth trajectory of brain tissue, decreased size of selective brain structures, particularly the corpus callosum, frontal cortex, hippocampus, amygdala, and cerebellum, and decreased ventromedial subcallosal NAA and choline.
Aim 2 : Use in vivo MR to determine if P and HAD-1 rats are more robust to deleterious effects of high binge and withdrawal alcohol exposure than their NP and LAD-1 counterparts and their W and N/NIH selection stock. Hypothesis: The magnitude of the MRI and MRSabnormalities will be NP> W> Pand LAD-1 > N/NIH > HAD-1.
Aim 3 : Identify histological and explore gene expression correlates of alcohol-induced brain damage and determine if alcohol-induced brain damage occurs below the limits of detection of in vivo MR studies. Hypothesis: Compared with controls, alcohol-exposed animals will have reduced callosal size, thinner myelin sheathes, and lower neuron counts in gray matter regions predicted to sustain MR-detectable damage.
Aim 4 : As a resource, provide MR imaging expertise to other INIA-West and INIA-East investigators for invivo studies of animal models of alcoholism.
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