Maturation of reward, affect and behavioral control coincides with morphological changes in frontal and limbic brain regions during adolescence and the transition to adulthood. Previous studies from our lab have shown that adolescent rats are far more sensitive to ethanol-induced forebrain neurodegeneration and to inhibition of hippocampal neurogenesis. We have also observed in adult mice that adolescent ethanol exposure reduced the volume of the forebrain and several other regions as determined by MRI. In addition to a reduction in MRI volume, histological measurements indicated corresponding reduction of forebrain area and decreased cholinergic neuron density. These pathological changes were associated with functional deficits in reversal learning. This Research Component-7 of the NADIA consortium will extend these studies to determine the long-term consequences of adolescent alcohol exposure. This NADIA Research Component- 7 hypothesizes that adolescent intermittent ethanol (AIE) treatment will alter adult brain regional cellular structure, neurogenesis, microglia, astrocyte phenotypes and myelin, as well as brain regional MRI volumes and histologic areas. Additional hypotheses are that higher alcohol doses, younger individuals and longer periods of abuse will cause more pathology and will be reflected in diffuse neurocircuitry responses to stress and ethanol challenges. It is further hypothesized that AIE will alter stress and alcohol induction of neuronal activation markers in adults. The following 4 Aims test hypotheses:
Aim 1 will test the hypothesis that AIE alters adult brain neurogenesis and neuroprogenitor-stem cells (NPC).
Aim 2 will test the hypothesis that AIE alters adult brain white matter.
Aim 3 will determine if AIE alters adult brain microglia and astrocytes.
Aim 4 will determine if AIE alters adult brain neuronal responses to stress or ethanol. The proposed studies will be conducted using different AIE protocols that vary age of ethanol exposure, e.g. youth-adolescent-young adult (P25-55), and dose;i.e. binge, heavy and moderate self-administration. Adults following AIE, are assessed for cognition (Barnes maze, learning and reversal learning), affect-anxiety behaviors (elevated plus maze), open field test (center time anxiety-overall locomotor) and social interaction (anxiety). Histochemistry on adult brain cellular structure and composition will be related to MRI regional volumes, DTI structure and behavior. In addition, studies will challenge adult rats with ethanol or stress to investigate neurocircuitry through IHC for neuronal activation markers (e.g. fos, zif268, pERK1/2, pDARPP). It is expected that AIE will have brain region specific effects with younger ages of AIE treatment inducing larger changes in adult brain cell structure. These studies will determine if models of underage drinking result in persistent structural, cellular, and neuronal activation responses that impact adult brain networks and behavior.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA020023-05
Application #
8706669
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Regunathan, Soundar
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zou, Jian Y; Crews, Fulton T (2014) Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS One 9:e87915
Gass, Justin T; Glen Jr, William Bailey; McGonigal, Justin T et al. (2014) Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood. Neuropsychopharmacology 39:2570-83
Coleman Jr, Leon Garland; Liu, Wen; Oguz, Ipek et al. (2014) Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility. Pharmacol Biochem Behav 116:142-51
Broadwater, Margaret A; Liu, Wen; Crews, Fulton T et al. (2014) Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure. Dev Neurosci 36:297-305
Lee, Joohwi; Lyu, Ilwoo; Styner, Martin (2014) Multi-atlas segmentation with particle-based group-wise image registration. Proc SPIE Int Soc Opt Eng 9034:903447
Qin, Liya; Crews, Fulton T (2014) Focal thalamic degeneration from ethanol and thiamine deficiency is associated with neuroimmune gene induction, microglial activation, and lack of monocarboxylic acid transporters. Alcohol Clin Exp Res 38:657-71
Ehlers, C L; Liu, W; Wills, D N et al. (2013) Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood. Neuroscience 244:1-15
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
Qin, Liya; Liu, Yuxin; Hong, Jau-Shyong et al. (2013) NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia 61:855-68
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

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