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

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.

Hyper-oligodendrogenesis at the vascular niche and reduced blood–brain barrier integrity in the prefrontal cortex during protracted abstinence

“…To determine the distribution of newly born oligodendroglia, mPFC sections were immunoprobed for both BrdU and PECAM-1 (gift from Dr. Peter Newman), followed by biotinylated secondary and fluorescent labeling via tyramide signal amplification. Confocal analysis was conducted with Zeiss Axiovert 100M (Kim & Mandyam, 2014; Kim et al, 2014; Somkuwar et al, 2015). Note, PECAM-1 expression is not contingent on the functional integrity of endothelium (for review, (Newman, 1994)).…”

“…Disrupted oligodendroglial homeostasis in the medial prefrontal cortex (mPFC) was associated with escalated ethanol intake in CIE rats (Richardson et al , 2009; Somkuwar et al , 2015). Specifically, high ethanol intake was shown to reduce proliferation of stem-like cells in several areas of the adult rodent brain, including mPFC (Nixon & Crews, 2002; Crews & Nixon, 2009; Richardson et al , 2009; Hansson et al , 2010).…”

“…Specifically, high ethanol intake was shown to reduce proliferation of stem-like cells in several areas of the adult rodent brain, including mPFC (Nixon & Crews, 2002; Crews & Nixon, 2009; Richardson et al , 2009; Hansson et al , 2010). During early ethanol abstinence (3-7 days), compensatory hyperproliferation of stem cells was observed in several brain regions (Nixon & Crews, 2004; Hansson et al , 2010), including the mPFC (Somkuwar et al , 2015). These newly born neural cells in the mPFC survived and differentiated, primarily (>85%) into new oligodendrocytes (Somkuwar et al , 2015).…”

“…During early ethanol abstinence (3-7 days), compensatory hyperproliferation of stem cells was observed in several brain regions (Nixon & Crews, 2004; Hansson et al , 2010), including the mPFC (Somkuwar et al , 2015). These newly born neural cells in the mPFC survived and differentiated, primarily (>85%) into new oligodendrocytes (Somkuwar et al , 2015). This increased/rebound oligodendrogenesis was associated with increased ethanol drinking (Somkuwar et al , 2015), increased ethanol seeking and decreased neuronal activation as measured by Fos expression in the mPFC after prolonged abstinence (Somkuwar et al , 2016).…”

“…These newly born neural cells in the mPFC survived and differentiated, primarily (>85%) into new oligodendrocytes (Somkuwar et al , 2015). This increased/rebound oligodendrogenesis was associated with increased ethanol drinking (Somkuwar et al , 2015), increased ethanol seeking and decreased neuronal activation as measured by Fos expression in the mPFC after prolonged abstinence (Somkuwar et al , 2016). Voluntary wheel running (WR) during prolonged abstinence did not alter ethanol drinking, but inhibited ethanol seeking, increased mPFC neuronal activation and rescued mPFC oligodendroglial homeostasis (Somkuwar et al , 2016).…”