This competing renewal application, U01 AA013521, Neuroimaging of Alcohol-Induced Neuroadaptation: Translation from Animals to Humans, is submitted in response to RFA-AA-16-004 (U01). The overarching aim of this proposal is to identify in vivo markers related to the pathogenesis of alcohol use disorder (AUD) related to altered stress (amygdala) circuitry and neuroimmune recruitment. Recent resting- state functional magnetic resonance imaging (rs-fMRI) studies will determine the differential circuitry of the amygdala as a function of withdrawal frequency in AUD. The potential for neuroimmune recruitment in AUD pathology will be evaluated using a multi-B-value diffusion tensor imaging (DTI) analysis of free water, which is proposed as an index of neuroinflammation. These in vivo biomarkers will be collected in humans, monkeys, and rodents and contribute to the validity of the animal models and provide a framework for evaluating pharmacological agents to aid in AUD recovery. Optogenetic stimulated functional MRI in rodents will further explore specific brain circuits relevant to AUD.
Specific Aim 1 will use rs-fMRI and multi-B-value DTI in humans with AUD and their controls to test the hypothesis that greater withdrawal frequency will be associated with more symptoms of anxiety, changes in amygdala rs-fMRI connectivity (stronger functional connectivity between the CMA and anterior cingulate cortex [ACC] and between BLA and anterior insula; weaker connectivity between the CMA and posterior cingulate cortex [PCC]), and more free water in amygdala, hippocampus, and cingulate cortex.
Specific Aim 2 will analyze rs-fMRI and multi-B-value DTI data in monkeys at baseline and following 3 cycles of EtOH exposure and withdrawal collected by INIA-Stress to test the hypothesis that greater withdrawal frequency will be associated with exacerbated anxiety, higher EtOH consumption, changes in amygdala rs-fMRI connectivity, and more free water in amygdala, hippocampus, and cingulate cortex.
Specific Aim 3 will rs-fMRI and multi-B-value DTI in rats exposed to chronic intermittent ethanol (CIE) via vapor chambers to test the hypothesis that longer periods of CIE will result in the accrual of anxiety-like behavior, stronger functional connectivity between the amygdala and downstream targets (e.g., brainstem), and more free water in amygdala, hippocampus, and cingulate cortex. It is also hypothesized that apremilast, a phosphodiesterase-4 inhibitor will normalize affected behavioral, functional, and free water changes, thereby supporting neuroimmune mechanisms in AUD.
Specific Aim 4 will use optogenetic and chemogenetic methods and fMRI to determine the neurocircuitry recruited by direct stimulation of the rat central nucleus of the amygdala (CeA) corticotropin releasing factor (CRF) neurons. The hypothesis to be tested is that direct stimulation of CeA CRF neurons will result in similar functional connectivity patterns as observed following multiple CIE exposures.

Public Health Relevance

The goal of this translational neuroimaging proposal conducted in humans, monkeys, and rats is to provide in vivo biomarkers of mechanisms contributing to Alcohol Use Disorder (AUD) pathogenesis. Diffusion tensor and resting state magnetic resonance brain imaging (MRI) will be used to differentiate direct and functional neural circuitry as it is affected by acute alcohol and chronic alcoholic withdrawal. Optogenetic stimulated functional MRI in rodents will further explore specific brain circuits relevant to AUD. Established biomarkers will be used to evaluate mechanisms of action of novel strategies to treat alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA013521-19
Application #
9863978
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Matochik, John A
Project Start
2001-09-27
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Zahr, Natalie M (2018) The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. Front Aging Neurosci 10:56
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
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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