Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex

Abstract

The therapeutic effects of wheel running (WR) during abstinence on reinstatement of ethanol seeking behaviors in rats that self-administered ethanol only (ethanol drinking, ED) or ED with concurrent chronic intermittent ethanol vapor experience (CIE-ED) were investigated. Neuronal activation as well as oligodendroglial and neuroinflammatory factors were measured in the medial prefrontal cortex (mPFC) tissue to determine cellular correlates associated with enhanced ethanol seeking. CIE-ED rats demonstrated escalated and unregulated intake of ethanol and maintained higher drinking than ED rats during abstinence. CIE-ED rats were more resistant to extinction from ethanol self-administration, however, demonstrated similar ethanol seeking triggered by ethanol contextual cues compared to ED rats. Enhanced seeking was associated with reduced neuronal activation, and increased number of myelinating oligodendrocyte progenitors and PECAM-1 expression in the mPFC, indicating enhanced oligodendroglial and neuroinflammatory response during abstinence. WR during abstinence enhanced self-administration in ED rats, indicating a deprivation effect. WR reduced reinstatement of ethanol seeking in CIE-ED and ED rats, indicating protection against relapse. The reduced ethanol seeking was associated with enhanced neuronal activation, reduced number of myelinating oligodendrocyte progenitors, and reduced PECAM-1 expression. The current findings demonstrate a protective role of WR during abstinence in reducing ethanol seeking triggered by ethanol contextual cues and establish a role for oligodendroglia-neuroinflammatory response in ethanol seeking. Taken together, enhanced oligodendroglia-neuroinflammatory response during abstinence may contribute to brain trauma in chronic alcohol drinking subjects and be a risk factor for enhanced propensity for alcohol relapse.

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

“…Effects of history of ethanol experience and access to running wheel during ethanol abstinence on the oligo-vascular homeostasis in the mPFC was investigated to provide potential mechanistic link between the behavioral protection against ethanol seeking and the neuro-adaptive effects of wheel running during abstinence (Somkuwar et al , 2016). The experimental design is presented schematically (Figure 1).…”

“…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).…”

“…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). Since oligodendroglial turnover and maturation depends on cerebrovascular health (Arai & Lo, 2009; Miyamoto et al , 2014; Maki et al , 2015), it was not surprising that a cerebral endothelial marker, platelet/endothelial cell adhesion molecule-1 (PECAM-1 or CD-31), was also increased in association with the increased ethanol seeking, and these alterations were reduced by wheel running (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). Since oligodendroglial turnover and maturation depends on cerebrovascular health (Arai & Lo, 2009; Miyamoto et al , 2014; Maki et al , 2015), it was not surprising that a cerebral endothelial marker, platelet/endothelial cell adhesion molecule-1 (PECAM-1 or CD-31), was also increased in association with the increased ethanol seeking, and these alterations were reduced by wheel running (Somkuwar et al , 2016). However, it is unclear whether the oligodendroglial hyperproliferation is connected functionally to compromised cerebrovascular health in this model of AUD.…”

“…The mPFC tissue from rats previously found to exhibit enhanced oligodendrogenesis and increased ethanol seeking after prolonged abstinence (Somkuwar et al , 2016) was used for the current study. The relative localization of PECAM-1 and the newly born oligodendrocyte was conducted to understand the anatomical relation between the damaged endothelium and oligodendrogenesis.…”