Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons.
Hippocampal neurogenesis is known as the formation of new neurons from the proliferating neural progenitor cells (NPC) at the dentate gyrus. Cell proliferation, survival, differentiation and maturation are critical stages leading to the generation of healthy neurons. As all of these stages can be influenced by alcohol exposure, we studied the effects of chronic alcohol on each process by immunocytochemistry for stage-specific antigens and prelabelling newborn cells with bromodeoxyuridine (BrdU). Rats were administered alcohol liquid diet or control diet for one, two or four weeks. We found that cell proliferation was inhibited as proliferating cell nuclear antigen (PCNA) expression was reduced by approximately 50% in alcohol-treated animals at all time points. Doublecortin (DCX), a microtubule protein expressed early in differentiating neurons, was progressively decreased over the duration of exposure and significantly reduced after two and four weeks of drinking. Morphological analyses of DCX-positive cells revealed that four weeks of alcohol treatment reduced the size of the dendritic tree including the total length of apical dendrites, number of nodes and endings. Furthermore, BrdU labelling demonstrated a dramatic decrease in cell survival after four weeks of drinking, while cell death was increased by such treatment. Confocal analysis indicated that over 80% of BrdU+ cells colabelled with NeuN suggesting that alcohol reduced neurogenesis. In conclusion, chronic alcohol exposure disrupts neurogenesis by decreasing NPC proliferation, inhibiting cell survival and altering morphological maturation of newborn neurons. These data implicate impaired hippocampal neurogenesis with the cognitive and affective dysfunction associated with chronic alcoholism.
He
Jun
J
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Nixon
Kimberly
K
Shetty
Ashok K
AK
Crews
Fulton T
FT
D000437:Alcoholism / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D003713:Dendritic Cells / Q000473:pathology*; D018891:Dentate Gyrus / Q000473:pathology; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology / Q000473:pathology
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D018809:Proliferating Cell Nuclear Antigen