CoChat
Sign Up
Cited by 166Neurogenesis and neuroplasticity mechanismsPrenatal Substance Exposure EffectsMemory and Neural Mechanisms

Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning

Open access
Vetreno, Ryan P., Crews, Fulton T.·2015·Frontiers in Neuroscience
DOI 10.3389/fnins.2015.00035PMC PMC4325907
Open this paper in CoChat — free accountOpen PDF

Abstract

Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnins.2015.00035

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Persistent HC damage following intermittent alcohol exposure has been documented, with alcohol exposure in rats during the adolescent period leading to decreases in doublecortin labeled neurons, Ki-67 labeled cells, and BDNF, and increases in cleaved caspase-3 in the HC in adulthood.

    “Moreover, persistent HC damage following intermittent alcohol exposure has also been documented, with alcohol exposure in rats during the adolescent period leading to decreases in doublecortin labeled neurons (marker of neurogenesis), Ki-67 labeled cells (marker of cell proliferation), and BDNF, and increases in cleaved caspase-3 (marker of cell death) in the HC in adulthood (Vetreno and Crews 201”

    From The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse (2018) · cites this paper as Vetreno and Crews 2015

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Adolescent alcohol exposure inhibits neurogenesis throughout the hippocampus, produces long-lasting reductions in dendritic spine density and alterations in morphology, increases levels of astrocytic glial fibrillary acidic protein, and decreases levels of brain-derived neurotrophic factor.

    “Researchers have found that AAE inhibits neurogenesis throughout the hippocampus [64, 65], produces long-lasting reductions in dendritic spine density and alterations in morphology [66], increased levels of astrocytic glial fibrillary acidic protein (GFAP), and decreased levels of brain-derived neurotrophic factor (BDNF) [56].”

    From Consequences of adolescent drug use (2023) · cites this paper as [64]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 58 · Cited by 166

Research works printed but not linked: 48

  1. Abrous D. N. Koehl M. Le Moal M. (2005). Adult neurogenesis: from precursors to network and physiology. Physiol. Rev. 85, 523– 569. 10.1152/physrev.00055.2003 15788705 · DOI · Paper page
  2. Aggleton J. P. Brown M. W. (2005). Contrasting hippocampal and perirhinal cortex function using immediate early gene imaging. Q. J. Exp. Psychol. B 58, 218– 233. 10.1080/02724990444000131 16194966 · DOI
  3. Antunes M. Biala G. (2012). The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn. Process. 13, 93– 110. 10.1007/s10339-011-0430-z 22160349 PMC3332351 · DOI · Paper page
  4. Bartolini L. Casamenti F. Pepeu G. (1996). Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions. Pharmacol. Biochem. Behav. 53, 277– 283. 10.1016/0091-3057(95)02021-7 8808132 · DOI
  5. Beynon S. B. Walker F. R. (2012). Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225, 162– 171. 10.1016/j.neuroscience.2012.07.029 22824429 · DOI
  6. Broadwater M. A. Liu W. Crews F. T. Spear L. P. (2014). Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure. Dev. Neurosci. 36, 297– 305. 10.1159/000362874 24993092 PMC4125431 · DOI
  7. Brown J. P. Couillard-Despres S. Cooper-Kuhn C. M. Winkler J. Aigner L. Kuhn H. G. (2003). Transient expression of doublecortin during adult neurogenesis. J. Comp. Neurol. 467, 1– 10. 10.1002/cne.10874 14574675 · DOI
  8. Cooper-Kuhn C. M. Winkler J. Kuhn H. G. (2004). Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J. Neurosci. Res. 77, 155– 165. 10.1002/jnr.20116 15211583 · DOI
  9. Cotman C. W. Berchtold N. C. (2002). Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25, 295– 301. 10.1016/S0166-2236(02)02143-4 12086747 · DOI · Paper page
  10. Crews F. He J. Hodge C. (2007). Adolescent cortical development: a critical period of vulnerability for addiction. Pharmacol. Biochem. Behav. 86, 189– 199. 10.1016/j.pbb.2006.12.001 17222895 PMC11646682 · DOI · Paper page
  11. Crews F. Nixon K. Kim D. Joseph J. Shukitt-Hale B. Qin L.. (2006a). BHT blocks NF-kappaB activation and ethanol-induced brain damage. Alcohol. Clin. Exp. Res. 30, 1938– 1949. 10.1111/j.1530-0277.2006.00239.x 17067360 · DOI
  12. Crews F. T. Nixon K. Wilkie M. E. (2004). Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol 33, 63– 71. 10.1016/j.alcohol.2004.04.005 15353174 · DOI
  13. Cummings D. M. Snyder J. S. Brewer M. Cameron H. A. Belluscio L. (2014). Adult neurogenesis is necessary to refine and maintain circuit specificity. J. Neurosci. 34, 13801– 13810. 10.1523/JNEUROSCI.2463-14.2014 25297106 PMC4188975 · DOI
  14. Dewit D. J. Adlaf E. M. Offord D. R. Ogborne A. C. (2000). Age at first alcohol use: a risk factor for the development of alcohol disorders. Am. J. Psychiatry 157, 745– 750. 10.1176/appi.ajp.157.5.745 10784467 · DOI · Paper page
  15. Ehlers C. L. Liu W. Wills D. N. Crews F. T. (2013). Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood. Neuroscience 244, 1– 15. 10.1016/j.neuroscience.2013.03.058 23567812 PMC3726260 · DOI
  16. Eriksson P. S. Perfilieva E. Bjork-Eriksson T. Alborn A. M. Nordborg C. Peterson D. A.. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313– 1317. 10.1038/3305 9809557 · DOI · Paper page
  17. Gould E. Beylin A. Tanapat P. Reeves A. Shors T. J. (1999a). Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260– 265. 10.1038/6365 10195219 · DOI · Paper page
  18. Gould E. Reeves A. J. Fallah M. Tanapat P. Gross C. G. Fuchs E. (1999b). Hippocampal neurogenesis in adult Old World primates. Proc. Natl. Acad. Sci. U.S.A. 96, 5263– 5267. 10220454 PMC21852
  19. He J. Crews F. T. (2007). Neurogenesis decreases during brain maturation from adolescence to adulthood. Pharmacol. Biochem. Behav. 86, 327– 333. 10.1016/j.pbb.2006.11.003 17169417 · DOI · Paper page
  20. He J. Nixon K. Shetty A. K. Crews F. T. (2005). Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons. Eur. J. Neurosci. 21, 2711– 2720. 10.1111/j.1460-9568.2005.04120.x 15926919 · DOI
  21. Klempin F. Kempermann G. (2007). Adult hippocampal neurogenesis and aging. Eur. Arch. Psychiatry Clin. Neurosci. 257, 271– 280. 10.1007/s00406-007-0731-5 17401726 · DOI
  22. Kotani S. Yamauchi T. Teramoto T. Ogura H. (2006). Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats. Neuroscience 142, 505– 514. 10.1016/j.neuroscience.2006.06.035 16889901 · DOI
  23. Kuhn H. G. Dickinson-Anson H. Gage F. H. (1996). Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027– 2033. 8604047 PMC6578509
  24. Madsen T. M. Kristjansen P. E. Bolwig T. G. Wortwein G. (2003). Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 119, 635– 642. 10.1016/S0306-4522(03)00199-4 12809684 · DOI
  25. Mathieu P. Battista D. Depino A. Roca V. Graciarena M. Pitossi F. (2010). The more you have, the less you get: the functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain. J. Neurochem. 112, 1368– 1385. 10.1111/j.1471-4159.2009.06548.x 20028453 · DOI
  26. Mohapel P. Leanza G. Kokaia M. Lindvall O. (2005). Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol. Aging 26, 939– 946. 10.1016/j.neurobiolaging.2004.07.015 15718053 · DOI
  27. O'Malley P. M. Johnston L. D. Bachman J. G. (1998). Alcohol use among adolescents. Alcohol Health Res. World 22, 85– 93. 15706782 PMC6761813
  28. Pascual M. Blanco A. M. Cauli O. Minarro J. Guerri C. (2007). Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur. J. Neurosci. 25, 541– 550. 10.1111/j.1460-9568.2006.05298.x 17284196 · DOI · Paper page
  29. Paxinos G. Watson C. (1998). The Rat Brain in Stereotaxic Coordinates. San Diego, CA: Academic Press.
  30. Revest J. M. Dupret D. Koehl M. Funk-Reiter C. Grosjean N. Piazza P. V.. (2009). Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol. Psychiatry 14, 959– 967. 10.1038/mp.2009.15 19255582 · DOI · Paper page
  31. Richardson R. M. Sun D. Bullock M. R. (2007). Neurogenesis after traumatic brain injury. Neurosurg. Clin. N. Am. 18, 169– 181, xi. 10.1016/j.nec.2006.10.007 17244562 · DOI
  32. Rolls A. Shechter R. London A. Ziv Y. Ronen A. Levy R.. (2007). Toll-like receptors modulate adult hippocampal neurogenesis. Nat. Cell Biol. 9, 1081– 1088. 10.1038/ncb1629 17704767 · DOI
  33. Scholzen T. Gerdes J. (2000). The Ki-67 protein: from the known and the unknown. J. Cell. Physiol. 182, 311– 322. 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9 10653597 · DOI
  34. Sierra A. Encinas J. M. Maletic-Savatic M. (2011). Adult human neurogenesis: from microscopy to magnetic resonance imaging. Front. Neurosci. 5: 47. 10.3389/fnins.2011.00047 21519376 PMC3075882 · DOI
  35. Spalding K. L. Bergmann O. Alkass K. Bernard S. Salehpour M. Huttner H. B.. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219– 1227. 10.1016/j.cell.2013.05.002 23746839 PMC4394608 · DOI · Paper page
  36. Suarez-Pereira I. Canals S. Carrion A. M. (2015). Adult newborn neurons are involved in learning acquisition and long-term memory formation: the distinct demands on temporal neurogenesis of different cognitive tasks. Hippocampus 25, 51– 61. 10.1002/hipo.22349 25139443 · DOI
  37. Taffe M. A. Kotzebue R. W. Crean R. D. Crawford E. F. Edwards S. Mandyam C. D. (2010). Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates. Proc. Natl. Acad. Sci. U.S.A. 107, 11104– 11109. 10.1073/pnas.0912810107 20534463 PMC2890755 · DOI
  38. Treit D. Fundytus M. (1988). Thigmotaxis as a test for anxiolytic activity in rats. Pharmacol. Biochem. Behav. 31, 959– 962. 10.1016/0091-3057(88)90413-3 3252289 · DOI
  39. Van Praag H. Shubert T. Zhao C. Gage F. H. (2005). Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680– 8685. 10.1523/JNEUROSCI.1731-05.2005 16177036 PMC1360197 · DOI · Paper page
  40. Vetreno R. P. Broadwater M. Liu W. Spear L. P. Crews F. T. (2014). Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain. PLoS ONE 9: e113421 10.1371/journal.pone.0113421 25405505 PMC4236188 · DOI
  41. Vetreno R. P. Qin L. Crews F. 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. 10.1016/j.nbd.2013.07.002 23867237 PMC3775891 · DOI
  42. Wechsler H. Dowdall G. W. Davenport A. Castillo S. (1995). Correlates of college student binge drinking. Am. J. Public Health 85, 921– 926. 10.2105/AJPH.85.7.921 7604914 PMC1615519 · DOI
  43. White A. M. Swartzwelder H. S. (2004). Hippocampal function during adolescence: a unique target of ethanol effects. Ann. N. Y. Acad. Sci. 1021, 206– 220. 10.1196/annals.1308.026 15251891 · DOI
  44. Whitney N. P. Eidem T. M. Peng H. Huang Y. Zheng J. C. (2009). Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. J. Neurochem. 108, 1343– 1359. 10.1111/j.1471-4159.2009.05886.x 19154336 PMC2707502 · DOI
  45. Windle M. Spear L. P. Fuligni A. J. Angold A. Brown J. D. Pine D.. (2008). Transitions into underage and problem drinking: developmental processes and mechanisms between 10 and 15 years of age. Pediatrics 121 Suppl. 4, S273– S289. 10.1542/peds.2007-2243C 18381494 PMC2892675 · DOI
  46. Zhao C. Deng W. Gage F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell 132, 645– 660. 10.1016/j.cell.2008.01.033 18295581 · DOI · Paper page
  47. Zhao C. Teng E. M. Summers R. G. Jr. Ming G. L. Gage F. H. (2006). Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3– 11. 10.1523/JNEUROSCI.3648-05.2006 16399667 PMC6674324 · DOI · Paper page
  48. Zou J. Crews F. T. (2012). Inflammasome-IL-1beta signaling mediates ethanol inhibition of hippocampal neurogenesis. Front. Neurosci. 6: 77. 10.3389/fnins.2012.00077 22661925 PMC3362805 · DOI

Authors
Vetreno, R. P., & Crews, F. T.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Vetreno, Ryan P.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2015-02-12
Volume
9
Pages
35-35
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2015.00035
PMC
PMC4325907
OpenAlex
W2008509697
Cited by
166
References
58
Citations by year
2026: 5 · 2025: 13 · 2024: 10 · 2023: 14 · 2022: 12 · 2021: 24 · 2020: 16 · 2019: 19 · 2018: 16 · 2017: 19 · 2016: 13 · 2015: 5
FWCI
7.16
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UNC Libraries
Funders
  • Center for Alcohol Studies
  • National Institutes of Health (AA-11605, AA007573, AA019767)
  • National Institute on Alcohol Abuse and Alcoholism (P50AA011605, U24AA020022, U01AA020023, L40 AA021590, F32AA021040, U24AA020024, U54AA019767, P60AA011605, T32AA007573)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
hippocampal neurogenesis, dentate gyrus, doublecortin, neuroimmune signaling, TLR4, high mobility group box 1, lipopolysaccharide, object recognition memory, cognitive impairment, cell death, caspase-3, Ki-67, brain maturation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review