The International Journal of Neuropsychopharmacology

Thematic Section: BDNF/Neurogenesis/Cell Differentiation

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

Anita C. Hanssona1, Kimberly Nixona2, Roberto Rimondinia3, Ruslan Damadzica1, Wolfgang H. Sommera1, Robert Eskaya1, Fulton T. Crewsa4 and Markus Heiliga1 c1

a1 Laboratory of Clinical and Translational Studies, NIH/NIAAA, Bethesda, MD, USA

a2 Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA

a3 Department of Pharmacology, University of Bologna, Italy

a4 Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA

Abstract

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.

(Received September 01 2009)

(Reviewed October 12 2009)

(Revised January 13 2010)

(Accepted February 10 2010)

(Online publication March 25 2010)

Correspondence:

c1 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 9386 Fax: +1 301 402 044 Email: markus.heilig@mail.nih.gov