Alcohol-induced cognitive deficits are associated with decreased circulating levels of the neurotrophin BDNF in humans and rats

Abstract

Chronic alcohol consumption is associated with neurocognitive and memory deficits, dramatically affecting plasticityand connectivity, with maximal expression as dementia. Neurotrophic factors may contribute to alcohol-related cogni-tive decline. For further investigation, a cross-sectional study was performed to evaluate the association of cognitiveimpairment, by using frontal assessment battery, and memory loss, using memory failures everyday, with the circulat-ing levels of the neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in abstinent sub-jects with alcohol use disorders (AUDs,N= 58, average of 17.9 years of problematic use and 4.3 months of abstinence)compared with healthy control subjects (N= 22). This association was also explored in a pre-clinical model of adoles-cent rats chronically exposed to alcohol up to adulthood (~77 days old) in a three-bottle free-choice (5–10–20 per-cent), repeated abstinence and relapse paradigm. AUD subjects had low educational level and cognitive impairmentassociated with teenage consumption and lower circulating levels of BDNF and NT-3. Only BDNF concentrationshowed a positive correlation with frontal assessment battery in AUD patients. In the ethanol-exposed rats, the plasmalevels of BDNF and NT-3 were also decreased, and a negative correlation between hippocampalBdnfmRNA levels andrecognition memory was found. The ethanol-exposed rat hippocampus showed a decrease in the mRNA levels of neu-rotrophic (BdnfandNtf-3) and neurogenic (Mki67,Sox2,Dcx,Ncam1andCalb1) factors, associated to a deactivation ofthe neurogenic regulator mitogen-activated protein kinase extracellular signal-regulated kinase. Results suggest a rel-evant role of BDNF/extracellular signal-regulated kinase 2 signaling in alcohol-induced cognitive impairment and sug-gest that early alcohol exposure-derived effects on cognition are associated with neurotrophin signaling deficits.