A study of human brain tissue has found that binge drinking during adolescence causes epigenetic changes that could be linked with the development of psychological problems and alcohol use disorder (AUD) in adulthood. The study, headed by researchers at the University of Illinois at Chicago (UIC) Center for Alcohol Research in Epigenetics, discovered that the brains of individuals who had started drinking before age 21 demonstrated epigenetic changes that altered the expression of a protein called brain-derived neurotrophic factor (BDNF), which is involved in the formation and maintenance of neural connections in the amygdala. This region of the brain controls emotions and decision making.

“The epigenetic changes we saw in the amygdala of early-onset drinkers can alter the normal function of the amygdala, which helps regulate our emotions, and may cause individuals to be more susceptible for things like anxiety, which we have shown in other studies, or the development and maintenance of alcohol use disorder later in life,” commented Subhash Pandey, PhD, professor of psychiatry and director of the UIC Center for Alcohol Research in Epigenetics. Pandey is corresponding author of the scientists’ published paper in Translational Psychiatry, which is titled, “The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders.”

Alcohol use disorders are chronic, debilitating psychiatric illnesses that are responsible for a considerable global socioeconomic and health burden, the authors commented. Starting to drink during adolescence is known to contribute to the likelihood and severity of AUDs later in life, “… as individuals who began drinking during adolescence are four times more likely to develop AUDs in adulthood.”

Adolescence is a key period in brain development, and adolescent drinking has been shown to increase activity in the amygdala, which leads to dampened executive control, increased emotional impulsivity, and alterations in decision-making. Adolescent drinkers also have a higher risk of engaging in risky behaviors and developing mental health problems in adulthood.

“During adolescence, the amygdala undergoes several key changes in specific inter- and intra-region connectivity, and this process is thought to be disrupted by alcohol use,” the authors continued. BDNF is critical to normal brain development, and is involved in the survival and differentiation of neurons. “… disruption to normal BDNF expression and signaling in adolescence is likely to produce detrimental outcomes on normal brain development,” the team continued. “Changes in BDNF signaling are likely to be involved in structural changes in the amygdala, which involve synaptic pruning and altered connectivity between the amygdala and other brain regions throughout the adolescent period.”

Recent research has implicated the BDNF in the development of alcohol dependence in adulthood, and emerged as what the team called “a critical molecular player in central nervous system (CNS) development, psychiatric disorders, and AUDs.”

Long noncoding RNAs (lncRNAs) are a form of RNA that are found almost exclusively in the brain, and are important in normal brain development. Most of those that have been studied are involved in regulating gene expression and chromatin structure, although the functions of the vast majority remain unknown. Interestingly, studies have indicated that lncRNAs may play an important role in AUDs in adults.

BDNF-antisense (BDNF-AS) is a lncRNA that negatively regulates BDNF production. The researchers’ newly reported studies were designed to investigate whether there was an association between BDNF-AS, BDNF, amygdala function, and AUD development in adults who started drinking during adolescence. “We aimed to determine if there are epigenetic changes mediated by BDNF-AS that are operative in the regulation of BDNF expression in adolescence, and whether these changes persist into adulthood in the amygdala of human postmortem brains diagnosed with AUDs that began drinking before the age of 21.”

To do this they accessed postmortem human amygdala tissue samples from the New South Wales Brain Tissue Resource Center in Sydney. They analyzed tissues from 11 individuals who started to drink heavily before age 21 years (early-onset drinkers), 11 individuals who started to drink consistently only after the age of 21 (late-onset drinkers), and another 22 individuals who had no history of alcohol use disorder. The average age of death was 58 years for those without AUD, 55 years for early-onset drinkers, and 59 years for late-onset drinkers.

The results showed that levels of BDNF-AS were about 30% higher in the amygdalae of early-onset drinkers, and levels of BDNF mRNA expression were significantly lower in these samples than in the control tissues. Amygdala samples from early-onset drinkers had 30–40% less BDNF than the control samples. In contrast, there were no changes, relative to controls, in BDNF or BDNF-AS levels in the brains of people who started drinking in their 20s or later. “There was no significant change in either BDNF mRNA or BDNF-AS expression in the late onset group,” the team confirmed.

“Intriguingly, we also found that BDNF-AS expression positively correlated with the amount of alcohol consumed using two different metrics of alcohol consumption (grams consumed per day at time of death and standard drinks per week),” they further pointed out. “One possibility is that earlier age of alcohol use may interact with later alcohol consumption to induce BDNF-AS expression.”

“BDNF is needed for normal development in the brain and for connections to form between neurons,” said Pandey, who is also a senior research career scientist at Jesse Brown VA Medical Center, Chicago. “If levels are lowered due to alcohol exposure, then the brain will not develop normally, and we see that in these brain samples where there are abnormalities in another synaptic gene, Arc, possibly making abnormal connections between neurons.” Arc is a downstream target of BDN, which is involved in synaptic plasticity, and is “a critical target of adolescent and adult alcohol exposure in rodent models,” the team explained.

Detailed analyses indicated that the increased levels of BDNF-AS in the amygdala of early-onset drinkers was linked with decreased RNA methylation of the BDNF-AS gene. “This study demonstrates that early age of onset of alcohol consumption increases BDNF-AS lncRNA expression induced via diminished RNA methylation, which triggers aberrant epigenetic mechanisms to produce deficits in BDNF signaling in the amygdala and possibly associated with pathophysiology of AUD,” the authors concluded. “… our present findings confirm the hypothesis that there would be changes in BDNF expression in a cohort of postmortem amygdala from AUD subjects that began drinking during adolescence, demonstrating a conserved pathway that may induce increased drinking and other psychiatric problems in adulthood caused by adolescent alcohol exposure.”

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