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.
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