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Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling

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Abstract

Effects of withdrawal from ethanol drinking in chronic intermittent ethanol vapor (CIE)-exposed dependent rats and air-exposed nondependent rats on proliferation and survival of progenitor cells in the hippocampus and the medial prefrontal cortex (mPFC) were investigated. Rats were injected with 5′-Bromo 2-deoxyuridine 72 h post-CIE to measure proliferation (2 h-old cells) and survival (29-day-old cells) of progenitors born during a time-point previously reported to elicit a proliferative burst in the hippocampus. Hippocampal and mPFC brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B receptor (TrkB) expression were measured 3 h or 21d post-CIE to evaluate neurotrophic signaling during a time point preceding the proliferative burst and survival of newly born progenitors. CIE rats demonstrated elevated drinking compared to nondependent rats and CIE rats maintained elevated drinking following protracted abstinence. Withdrawal from CIE increased BDNF levels in the hippocampus and mPFC, and subsequently increased proliferation in the hippocampus and mPFC compared to nondependent rats and controls. Protracted abstinence from CIE reduced BDNF expression to control levels, and subsequently reduced neurogenesis compared to controls and nondependent rats in the hippocampus. In the mPFC, protracted abstinence reduced BDNF expression to control levels, whereas increased oligodendrogenesis in dependent rats compared to nondependent rats and controls. These results suggest a novel relationship between BDNF and progenitors in the hippocampus and mPFC, in which increased ethanol drinking may alter hippocampal and cortical function in alcohol dependent subjects by altering the cellular composition of newly born progenitors in the hippocampus and mPFC.

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Acknowledgments

The study was supported by funds from the National Institute on Drug Abuse (DA022473 and DA034140 to CDM), National Institute on Alcoholism and Alcohol Abuse (NIAAA; AA020098 and AA06420 to CDM) and Alcohol Beverage Medical Research Foundation (to CDM), a NIAAA Pathway to Independence Award to SE (LSUHSC-New Orleans, AA020839), and T32AA00747 to MCS. We appreciate the technical support of Robert Lintz, Ilham Polis, and Maury Cole for assistance with operant self-administration studies and ethanol vapor chambers. We thank Atoosa Ghofranian from the independent study program at UCSD for assistance with tissue processing. We thank Drs. Charles Stiles and John Alberta, Harvard Medical School, for generously providing the Olig2 antibody. We thank Dr. Marian Lorgrip for critical reading of the manuscript. This is manuscript number 27067 from The Scripps Research Institute. The authors have no conflicts of interest to report.

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Somkuwar, S.S., Fannon, M.J., Staples, M.C. et al. Alcohol dependence-induced regulation of the proliferation and survival of adult brain progenitors is associated with altered BDNF-TrkB signaling. Brain Struct Funct 221, 4319–4335 (2016). https://doi.org/10.1007/s00429-015-1163-z

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