Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol.
Adult neurogenesis is a newly considered form of plasticity that could contribute to brain dysfunction in psychiatric disease. Chronic alcoholism, a disease affecting over 8% of the adult population, produces cognitive impairments and decreased brain volumes, both of which are partially reversed during abstinence. Clinical data and animal models implicate the hippocampus, a region important in learning and memory. In a model of alcohol dependence (chronic binge exposure for 4 d), we show that adult neurogenesis is inhibited during dependence with a pronounced increase in new hippocampal neuron formation after weeks of abstinence. This increase is attributable to a temporally and regionally specific fourfold increase in cell proliferation at day 7 of abstinence, with a majority of those cells surviving and differentiating at percentages similar to controls, effects that doubled the formation of new neurons. Although increases in cell proliferation correlated with alcohol withdrawal severity, proliferation remained increased when diazepam (10 mg/kg) was used to reduce withdrawal severity. Indeed, those animals with little withdrawal activity still show a twofold burst in cell proliferation at day 7 of abstinence. Thus, alcohol dependence and recovery from dependence continues to alter hippocampal plasticity during abstinence. Because neurogenesis may contribute to hippocampal function and/or learning, memory, and mood, compensatory neurogenesis and the return of normal neurogenesis may also have an impact on hippocampal structure and function. For the first time, these data provide a neurobiological mechanism that may underlie the return of human cognitive function and brain volume associated with recovery from addiction.
Nixon
Kimberly
K
Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Crews
Fulton T
FT
D020268:Alcohol-Induced Disorders, Nervous System / Q000473:pathology*; D000435:Alcoholic Intoxication / Q000473:pathology; D000818:Animals; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000166:cytology* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009416:Nerve Regeneration / Q000502:physiology*; D009479:Neuropeptides / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors
D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D001973:Bromodeoxyuridine; D003975:Diazepam