Longitudinal Brain Magnetic Resonance Imaging Study of the Alcohol-Preferring Rat. Part I: Adult Brain Growth Edith V. Sullivan, Elfar Adalsteinsson, Rohit Sood, Dirk Mayer, Richard Bell, William McBride, Ting-Kai Li, and Adolf Pfefferbaum Background: The alcohol-preferring (P) rat, a Wistar strain selectively bred to consume large amounts of alcohol voluntarily, has been used as an animal model of human alcoholism for 3 decades. Heretofore, knowledge about brain morphology has been confined to postmortem examination. Quantitative neuroimaging procedures make it feasible to examine the potential longitudinal effects of alcohol exposure in vivo, while controlling modifying factors, such as age, nutrition, and exercise. To date, few imaging studies have considered what morphological changes occur with age in the rodent brain, and none has systematically applied quantitative neuroimaging approaches to measure volume changes in regional brain structures over extended periods in the adult rat. Methods: We used structural magnetic resonance imaging (MRI) in a longitudinal design to examine 2 cohorts of adult P rats, never exposed to alcohol: Cohort A included 8 rats, 7 of which survived the entire study (578 days) and 4 MRI sessions; Cohort B included 9 rats, all of which survived the study (452 days) and 5 MRI sessions. Results: Growth in whole-brain volume reached maximal levels by about 450 days of age, whereas body weight continued its gain without asymptote. Growth was not uniform across the brain struc- tures measured. Over the initial 12 months of the study, the corpus callosum area expanded 36%, cerebellum 17%, and hippocampus 10%, whereas ventricle size was unchanged. Factors affecting growth rate estimates included litter effects, MR image signal-to-noise ratio, and measurement error. Conclusion: Unlike longitudinal human reports of regional volume declines in aging brain tissue, several brain structures in adult rats continued growing, and some growth patterns were litter- dependent. Determining normal regional growth patterns of brain and of the substantial variance exerted by litter differences, even in selectively bred rats, is essential for establishing baselines against which normal and aberrant dynamic changes can be detected in animal models of aging and disease. Key Words: Brain Growth, Rat, MRI, Morphology, Alcohol, Age. A NIMAL MODELS OF brain structure and function have become essential research tools in efforts to iso- late mechanisms causing neuropsychiatric disorders (e.g., Griffin, 2002; McKinney, 2001). In the case of alcoholism, the primary neurotoxin is known, but its effects on the brain can vary with multiple factors, including age (Card- enas et al., 2005; O’Neill et al., 2001; Pfefferbaum et al., 1992), sex (Hommer et al., 2001; Pfefferbaum et al., 2001), genetics (Edenberg et al., 2004), family history (Porjesz et al., 2005), nutrition (Harper and Butterworth, 1997; Lieber, 2003), withdrawal symptoms (Becker, 2000), age at exposure (Riley et al., 1995), treatment history (Fein and Landman, 2005), and individual dynamic history of absti- nence and relapse (Pfefferbaum et al., 1995). These factors are impossible to control and difficult to document in human studies of the natural course of alcoholism and highlight the worth of longitudinal animal studies in identifying and tracking the relative contribution of the relevant variables, which can be controlled in the labora- tory. In vivo magnetic resonance imaging (MRI) provides a host of noninvasive methods for quantifying character- istics of brain tissue type, morphology, function, and chemistry (for a review, see Adalsteinsson et al., 2002) From the Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California (EVS, AP); the Harvard-MIT Division of Health Sciences and Technology, MIT, Cam- bridge, Massachusetts (EA); the Department of Electrical Engineering and Computer Science, University of New Mexico Health Center, Albuquerque, New Mexico (EA); the Department of Neurology, University of New Mexico Health Center, Albuquerque, New Mexico (RS); the Department of Radiology, Stanford University School of Medicine, Stanford, California (DM); the Institute of Psychiatry, Indiana University Medical Center, Indianapolis, Indiana (RB); the Department of Psychiatry, Indiana University Medical Center, Indianapolis, Indiana (WM); the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (TKL); and the Neuroscience Program, SRI International, Menlo Park, California (AP). Received for publication November 29, 2005; accepted March 8, 2006. Support for this project was provided by the Integrative Neuroscience Initiative on Alcoholism (INIA) from the National Institute on Alcohol Abuse and Alcoholism (AA13521 and AA13522) and by NIAAA AA05965. Reprint requests: Adolf Pfefferbaum, MD, Neuroscience Program, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025; Fax: 650-859-2743; E-mail: dolf@synapse.sri.com Copyright r 2006 by the Research Society on Alcoholism. DOI: 10.1111/j.1530-0277.2006.00145.x Alcohol Clin Exp Res, Vol 30, No 7, 2006: pp 1234–1247 1234 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 30, No. 7 July 2006