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Long-term suppression of forebrain neurogenesis and loss of neuronal progenitor cells following prolonged alcohol dependence in rats

  • Anita C. Hansson (a1), Kimberly Nixon (a2), Roberto Rimondini (a3), Ruslan Damadzic (a1), Wolfgang H. Sommer (a1), Robert Eskay (a1), Fulton T. Crews (a4) and Markus Heilig (a1)
  • DOI:
  • Published online: 25 March 2010

Alcohol dependence leads to persistent neuroadaptations, potentially related to structural plasticity. Previous work has shown that hippocampal neurogenesis is modulated by alcohol, but effects of chronic alcohol on neurogenesis in the forebrain subventricular zone (SVZ) have not been reported. Effects in this region may be relevant for the impairments in olfactory discrimination present in alcoholism. Here, we examined the effects of prolonged alcohol dependence on neurogenesis. Rats were sacrificed directly after 7 wk of intermittent alcohol vapour exposure, or 3, 7 or 21 d into abstinence. Proliferation was assessed using BrdU and Ki67 immunoreactivity, newly differentiated neurons (neurogenesis) as doublecortin-immunoreactivity (DCX-IR), and neural stem cells using the SOX2 marker. In the dentate gyrus, chronic dependence resulted in a pattern similar to that previously reported for acute alcohol exposure: proliferation and neurogenesis were suppressed by the end of exposure, rebounded on day 3 of abstinence, and returned to control levels by days 7 and 21. In the SVZ, proliferation was also suppressed at the end of alcohol exposure, followed by a proliferation burst 3 d into abstinence. However, in this area, there was a trend for reduced proliferation on days 7 and 21 of abstinence, and this was accompanied by significant suppression of DCX-IR, indicating a long-term suppression of forebrain neurogenesis. Finally, a decrease in the SOX2 stem cell marker was detected at days 7 and 21, suggesting long-term reduction of the SVZ stem cell pool. While suppression of hippocampal neurogenesis by alcohol dependence is transient, the suppression in the forebrain SVZ appears long-lasting.

Corresponding author
Address for correspondence: M. Heilig, M.D., Ph.D., Laboratory of Clinical and Translational Studies, NIAAA/NIH, 10 Center Dr, Bethesda, MD, 20892-1108, USA. Tel.: +1 301 435 9386Fax: +1 301 402 044Email:
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E Aberg , CP Hofstetter , L Olson , S Brene (2005). Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse. International Journal of Neuropsychopharmacology 8, 557567.

A Alvarez-Buylla , DA Lim (2004). For the long run: maintaining germinal niches in the adult brain. Neuron 41, 683686.

M Bergami , R Rimondini , S Santi , R Blum , (2008). Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proceedings of the National Academy of Sciences USA 105, 1557015575.

A Bjornebekk , AA Mathe , S Brene (2009). The antidepressant effects of running and escitalopram are associated with levels of hippocampal NPY and Y1 receptor but not cell proliferation in a rat model of depression. Hippocampus. Published online: 21 July 2009. doi:10.1002/hipo.20683.

CY Brazel , TL Limke , JK Osborne , T Miura , (2005). Sox2 expression defines a heterogeneous population of neurosphere-forming cells in the adult murine brain. Aging Cell 4, 197207.

JP Brown , S Couillard-Despres , CM Cooper-Kuhn , J Winkler , (2003). Transient expression of doublecortin during adult neurogenesis. Journal of Comparative Neurology 467, 110.

FT Crews , T Buckley , PR Dodd , G Ende , (2005). Alcoholic neurobiology: changes in dependence and recovery. Alcoholism: Clinical and Experimental Research 29, 15041513.

FT Crews , K Nixon , ME Wilkie (2004). Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol 33, 6371.

MA Curtis , M Kam , U Nannmark , MF Anderson , (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 12431249.

DJ David , BA Samuels , Q Rainer , JW Wang , (2009). Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479493.

RS Duman , LM Monteggia (2006). A neurotrophic model for stress-related mood disorders. Biological Psychiatry 59, 11161127.

P Ellis , BM Fagan , ST Magness , S Hutton , (2004). SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Developmental Neuroscience 26, 148165.

V Episkopou (2005). SOX2 functions in adult neural stem cells. Trends in Neurosciences 28, 219221.

PS Eriksson , E Perfilieva , T Bjork-Eriksson , AM Alborn , (1998). Neurogenesis in the adult human hippocampus. Nature Medicine 4, 13131317.

J Gerdes , H Lemke , H Baisch , HH Wacker , (1984). Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. Journal of Immunology 133, 17101715.

JM Gilman , DW Hommer (2008). Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients. Addiction Biology 13, 423434.

JG Gleeson , PT Lin , LA Flanagan , CA Walsh (1999). Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23, 257271.

E Gould (2007). Opinion – how widespread is adult neurogenesis in mammals? Nature Reviews Neuroscience 8, 481488.

BF Grant , FS Stinson , DA Dawson , SP Chou , (2004). Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the national epidemiologic survey on alcohol and related conditions. Archives of General Psychiatry 61, 807816.

J He , K Nixon , AK Shetty , FT Crews (2005). Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons. European Journal of Neuroscience 21, 27112720.

L He , JC Marecki , G Serrero , FA Simmen , (2007). Dose-dependent effects of alcohol on insulin signaling: partial explanation for biphasic alcohol impact on human health. Molecular Endocrinology 21, 25412550.

M Heilig , GF Koob (2007). A key role for corticotropin-releasing factor in alcohol dependence. Trends in Neurosciences 30, 399406.

M Heilig , A Thorsell , WH Sommer , AC Hansson , (2009). Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues. Neuroscience & Biobehavioral Reviews. Published online: 24 November 2009. doi:10.1016/j.neubiorev.2009.11.018.

DG Herrera , AG Yague , S Johnsen-Soriano , F Bosch-Morell , (2003). Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Proceedings of the National Academy of Sciences USA 100, 79197924.

M Komitova , PS Eriksson (2004). Sox-2 is expressed by neural progenitors and astroglia in the adult rat brain. Neuroscience Letters 369, 2427.

C Mirescu , E Gould (2006). Stress and adult neurogenesis. Hippocampus 16, 233238.

K Nixon (2006). Alcohol and adult neurogenesis: roles in neurodegeneration and recovery in chronic alcoholism. Hippocampus 16, 287295.

K Nixon , FT Crews (2002). Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. Journal of Neurochemistry 83, 10871093.

K Nixon , FT Crews (2004). Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. Journal of Neuroscience 24, 97149722.

K Nixon , DH Kim , EN Potts , J He , (2008). Distinct cell proliferation events during abstinence after alcohol dependence: microglia proliferation precedes neurogenesis. Neurobiology of Disease 31, 218229.

LE O'Dell , AJ Roberts , RT Smith , GF Koob (2004). Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure. Alcoholism: Clinical and Experimental Research 28, 16761682.

G Paxinos , C Watson (2005). The Rat Brain in Stereotaxic Coordinates. Amsterdam: Elsevier Academic Press.

C Pittenger , RS Duman (2008). Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109.

A Quinones-Hinojosa , N Sanai , M Soriano-Navarro , O Gonzalez-Perez , (2006). Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. Journal of Comparative Neurology 494, 415434.

MS Rao , AK Shetty (2004). Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus. European Journal of Neuroscience 19, 234246.

R Rimondini , C Arlinde , W Sommer , M Heilig (2002). Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol. FASEB Journal 16, 2735.

AJ Roberts , CJ Heyser , M Cole , P Griffin , (2000). Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22, 581594.

CI Rupp , WW Fleischhacker , A Drexler , A Hausmann , (2006). Executive function and memory in relation to olfactory deficits in alcohol-dependent patients. Alcoholism: Clinical and Experimental Research 30, 13551362.

CI Rupp , WW Fleischhacker , A Hausmann , D Mair , (2004). Olfactory functioning in patients with alcohol dependence: impairments in odor judgements. Alcohol and Alcoholism 39, 514519.

CI Rupp , M Kurz , G Kemmler , D Mair , (2003). Reduced olfactory sensitivity, discrimination, and identification in patients with alcohol dependence. Alcoholism: Clinical and Experimental Research 27, 432439.

L Santarelli , M Saxe , C Gross , A Surget , (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805809.

WH Sommer , R Rimondini , AC Hansson , PA Hipskind , (2008). Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biological Psychiatry 63, 139145.

JR Stevenson , JP Schroeder , K Nixon , J Besheer , (2009). Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice. Neuropsychopharmacology 34, 12091222.

B Tabakoff , L Saba , K Kechris , W Hu , (2008). The genomic determinants of alcohol preference in mice. Mammalian Genome 19, 352365.

VA Vaidya , KC Vadodaria , S Jha (2007). Neurotransmitter regulation of adult neurogenesis: putative therapeutic targets. CNS & Neurological Disorders Drug Targets 6, 358374.

RA Walker (2006). Quantification of immunohistochemistry – issues concerning methods, utility and semiquantitative assessment I. Histopathology 49, 406410.

S Wicks , J Hammar , M Heilig , O Wisen (2001). Factors affecting the short-term prognosis of alcohol dependent patients undergoing inpatient detoxification. Substance Abuse 22, 235245.

DA Wilson , AR Best , RM Sullivan (2004). Plasticity in the olfactory system: lessons for the neurobiology of memory. Neuroscientist 10, 513524.

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