title: Chronic Alcohol Exposure is Associated with Decreased Neurogenesis, Aberrant Integration of Newborn Neurons, and Cognitive Dysfunction in Female Mice.
abstract: BACKGROUND
  Neurological deficits of alcohol use disorder (AUD) have been attributed to dysfunctions of specific brain structures. Studies of alcoholic patients and chronic alcohol exposure animal models consistently identify reduced hippocampal mass and cogntive dysfunctions as a key alcohol-induced brain adaptation. However, the precise substrate of chronic alcohol exposure that leads to structural and functional impairments of the hippocampus is largely unknown.
  
  
  METHODS
  Using a calorie-matched alcohol feeding method, we tested whether chronic alcohol exposure targets neural stem cells and neurogenesis in the adult hippocampus. The effect of alcohol on proliferation of neural stem cells as well as cell fate determination and survival of newborn cells was evaluated via bromodeoxyuridine pulse and chase methods. A retrovirus-mediated single-cell labeling method was used to determine the effect of alcohol on the morphological development and circuitry incorporation of individual hippocampal newborn neurons. Finally, novel object recognition (NOR) and Y-maze tests were performed to examine whether disrupted neurogenesis is associated with hippocampus-dependent functional deficits in alcohol-fed mice.
  
  
  RESULTS
  Chronic alcohol exposure reduced proliferation of neural stem cells and survival rate of newborn neurons; however, the fate determination of newborn cells remained unaltered. Moreover, the dendritic spine density of newborn neurons significantly decreased in alcohol-fed mice. Impaired spine formation indicates that alcohol interfered the synaptic connectivity of newborn neurons with excitatory neurons originating from various areas of the brain. In the NOR test, alcohol-fed mice displayed deficits in the ability to discriminate the novel object.
  
  
  CONCLUSIONS
  Our study revealed that chronic alcohol exposure disrupted multiple steps of neurogenesis, including the production and development of newborn neurons. In addition, chronic alcohol exposure altered connectivity of newborn neurons with other input neurons. Decreased neurogenesis and aberrant integration of newborn neurons into hippocampal networks are closely associated with deficits in hippocampus-dependent cognitive functions of alcohol-fed mice.
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Haleigh M
authors.initials: HM
authors.lastname: Golub
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Qi-Gang
authors.initials: QG
authors.lastname: Zhou
authors.affiliation: Neuroscience Program, Hamilton College, Clinton, New York.
authors.forename: Hannah
authors.initials: H
authors.lastname: Zucker
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Olga Nicole
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Eun Jeoung
authors.initials: EJ
authors.lastname: Ro
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Hoonkyo
authors.identifier: http://orcid.org/0000-0002-4227-2982
authors.initials: H
authors.lastname: Suh
mesh_terms: D000428:Alcohol Drinking / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced*; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D021641:Recognition, Psychology / Q000187:drug effects; D045442:Rotarod Performance Test
chemical_list: D000431:Ethanol
keywords: Alcohol; Dendritic Spines; Neurogenesis; Newborn Neurons; Recognition Memory