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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (70))
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Matochik, John A
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Sri International
Menlo Park
United States
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Zahr, Natalie M (2018) Peripheral TNF? elevations in abstinent alcoholics are associated with hepatitis C infection. PLoS One 13:e0191586
Sullivan, Edith V; Zahr, Natalie M; Sassoon, Stephanie A et al. (2018) The Role of Aging, Drug Dependence, and Hepatitis C Comorbidity in Alcoholism Cortical Compromise. JAMA Psychiatry 75:474-483
Pfefferbaum, Adolf; Zahr, Natalie M; Sassoon, Stephanie A et al. (2018) Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection. Biol Psychiatry Cogn Neurosci Neuroimaging 3:844-859
Zahr, Natalie M (2018) The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. Front Aging Neurosci 10:56
Fama, Rosemary; Le Berre, Anne-Pascale; Hardcastle, Cheshire et al. (2017) Neurological, nutritional and alcohol consumption factors underlie cognitive and motor deficits in chronic alcoholism. Addict Biol :
Zahr, Natalie M; Pfefferbaum, Adolf; Sullivan, Edith V (2017) Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders. Neuropharmacology 122:189-200
Zahr, Natalie M; Pfefferbaum, Adolf (2017) Alcohol's Effects on the Brain: Neuroimaging Results in Humans and Animal Models. Alcohol Res 38:183-206
Perez, Xiomara A; Zhang, Danhui; Bordia, Tanuja et al. (2017) Striatal D1 medium spiny neuron activation induces dyskinesias in parkinsonian mice. Mov Disord 32:538-548
Zahr, Natalie M; Sullivan, Edith V; Rohlfing, Torsten et al. (2016) Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo. Psychopharmacology (Berl) 233:2675-86
Zahr, Natalie M; Rohlfing, Torsten; Mayer, Dirk et al. (2016) Transient CNS responses to repeated binge ethanol treatment. Addict Biol 21:1199-1216

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