Maturation of reward, affect, and behavioral control coincides with morphological changes in the frontal cortex and limbic brain regions during the transition from adolescence to adulthood. Alcohol consumption during adolescence is highly prevalent, but its impact on maturation is currently unknown. Previous studies from our laboratory have shown that adolescent rats are far more sensitive to ethanol-induced neurodegeneration and inhibition of hippocampal neurogenesis than adults. Adolescent binge ethanol exposure in mice was demonstrated to reduce forebrain volume and cholinergic cell populations in the nucleus basalis that was associated with reversal learning impairment on the Morris Water maze. Although binge drinking is common during adolescence, it is unknown whether alcohol exposure results in persistent changes to brain morphology. Furthermore, it is unknown if binge drinking during adolescence increases the likelihood of developing psychopathology in adulthood. This Postdoctoral Fellowship grant hypothesizes that adolescent intermittent ethanol (AIE) will persistently alter both cellular and morphological maturation of th frontal cortex and limbic system, which will culminate in altered adult cognitive and emotive function. The AIE paradigm will be used in the following 3 Aims:
Aim 1. Test the hypothesis that AIE induces persistent changes to adolescent brain morphology that continue into adulthood.
Aim 2. Test the hypothesis that adolescent intermittent ethanol (AIE) exposure alters adolescent and adult brain cellular composition and neurogenesis.
Aim 3. Test the hypothesis that adolescent intermittent ethanol (AIE) will result in alterations to neurocognitive function that wil be evident in adulthood. Following AIE treatment, neuroimaging will be used to assess brain integrity, cortical thickness, white matter tracts, and regional volumes in adolescent (P56) and adult (P80) rats (Aim 1). Immunohistochemistry will be performed to assess adolescent and adult brain neuronal/glial composition and neurogenesis (Aim 2). Adult rats exposed to AIE will be assessed on a measure of cognition (Barnes maze, spatial and reversal learning) or an emotive behavioral battery (forced swim, open-field, social interaction, elevated plus-maze [Aim3]). The innovative training approach, which involves guidance and instruction from experts in the field of neuroimaging (Styner and Oguz), immunohistochemistry (Crews), and behavioral assessment (Crews) as well as attendance of courses and seminars, will allow for an in depth assessment of the detrimental effects of adolescent alcohol abuse on brain maturation and function in adulthood. Indeed, persistent alterations in behavior, morphology, and brain histology following adolescent alcohol exposure could change attitudes regarding underage drinking and discover new etiological mechanisms of adult brain pathology and mental illness.

Public Health Relevance

Adolescent use of alcohol represents a major public health concern with potential long-lasting impact on health care in the U.S. The adolescent period is characterized by considerable brain development and maturation. Since alcohol affects adolescent brain function differently than adults, it is imperative to determine if exposure during this maturational period confers persistent brain changes that continue into adulthood.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Regunathan, Soundar
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University of North Carolina Chapel Hill
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Crews, Fulton T; Vetreno, Ryan P (2016) Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology (Berl) 233:1543-57
Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz et al. (2016) Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction. Addict Biol 21:939-53
Crews, Fulton T; Vetreno, Ryan P; Broadwater, Margaret A et al. (2016) Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev 68:1074-1109
Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz et al. (2016) Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment. Addict Biol :
Vetreno, Ryan P; Crews, Fulton T (2015) Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning. Front Neurosci 9:35
Vetreno, Ryan P; Broadwater, Margaret; Liu, Wen et al. (2014) Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain. PLoS One 9:e113421
Crews, Fulton T; Qin, Liya; Sheedy, Donna et al. (2013) High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry 73:602-12
Vetreno, Ryan P; Qin, Liya; Crews, Fulton T (2013) Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol Dis 59:52-62
Vetreno, R P; Crews, F T (2012) Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and Toll-like receptors in the adult prefrontal cortex. Neuroscience 226:475-88
Crews, Fulton T; Vetreno, Ryan Peter (2011) Addiction, adolescence, and innate immune gene induction. Front Psychiatry 2:19