Emerging evidence suggests that people with alcohol use disorders are at higher risk for SARS-CoV-2. SARS-CoV-2 engages angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors for cellular entry. While ACE2 and TMPRSS2 genes are upregulated in the cortex of alcohol-dependent individuals, information on expression in specific brain regions and neural populations implicated in SARS-CoV-2 neuroinvasion, particularly monoaminergic neurons, is limited. We sought to clarify how chronic alcohol exposure affects ACE2 and TMPRSS2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points. C57BL/6J mice were exposed to chronic intermittent ethanol (CIE) vapor for 4 weeks and brains were examined using immunofluorescence. We observed increased ACE2 levels in the olfactory bulb and hypothalamus following CIE, which are known to mediate SARS-CoV-2 neuroinvasion. Total ACE2 immunoreactivity was also elevated in the raphe magnus (RMG), raphe obscurus (ROB), and locus coeruleus (LC), while in the dorsal raphe nucleus (DRN), ROB, and LC we observed increased colocalization of ACE2 with monoaminergic neurons. ACE2 also increased in the periaqueductal gray (PAG) and decreased in the amygdala. Whereas ACE2 was detected in most brain regions, TMPRSS2 was only detected in the olfactory bulb and DRN but was not significantly altered after CIE. Our results suggest that previous alcohol exposure may increase the risk of SARS-CoV-2 neuroinvasion and render brain circuits involved in cardiovascular and respiratory function as well as emotional processing more vulnerable to infection, making adverse outcomes more likely. Additional studies are needed to define a direct link between alcohol use and COVID-19 infection.

Adolescent alcohol use can permanently alter brain function and lead to poor health outcomes in adulthood. Emerging evidence suggests that alcohol use predispose to pain disorders or exacerbate existing pain conditions, but the neural mechanisms are currently unknown. Here we report that mice exposed to adolescent intermittent access to ethanol (AIE) exhibit increased pain sensitivity and depressive-like behaviors that persist after alcohol cessation and are accompanied by elevated CD68 expression in microglia and reduced numbers of serotonin (5-HT)-expressing neurons in the dorsal raphe nucleus (DRN). 5-HT expression was also reduced in the thalamus, anterior cingulate cortex (ACC) and amygdala as well as the lumbar dorsal horn of the spinal cord. We then found that chronic minocycline administration after AIE alleviated hyperalgesia and social deficits, while chemogenetic activation of microglia in the DRN of Cx3cr1-cre-GFP mice reproduced the effects of AIE on pain and social interaction. Taken together, these results indicate that microglial activation in the DRN may be a primary driver of pain and negative affect after AIE.

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). While 5-HTDRNneurons are generally thought to enhance social behavior, recent evidence suggests that specific 5-HT pathways can be aversive. Using chemogenetic iDISCO, the nucleus accumbens (NAcc) was identified as one of 5 regions that were activated by 5-HTDRNstimulation. We then employed an array of molecular genetic tools in transgenic mice to show that 5-HTDRNinputs to NAcc dynorphin neurons drive social avoidance in male mice after CIE by activating 5-HT2Creceptors. NAcc dynorphin neurons also inhibit dopamine release during social interaction, reducing the motivational drive to engage with social partners. This study reveals that excessive serotonergic drive after chronic alcohol can promote social aversion by inhibiting accumbal dopamine release. Drugs that boost brain serotonin levels may be contraindicated for individuals with AUD.

The molecular mechanism mediating nigrostriatal dopaminergic neurons degeneration in Parkinson's disease (PD) is not yet fully understood. We have shown that glia maturation factor (GMF), a proinflammatory protein mediated mast cells activation in the dopaminergic neurodegenerations. Here, we show that deficiency of GMF (GMF‐KO) and mast cell reduces the synergistic effects of mast cell proteases and calpain 1 dependent dopaminergic neuronal loss in the SN, and STR of the midbrain leads to improves motor behavioral impairments in an MPTP mouse model of PD. The MPTP induced nigrostriatal neurodegeneration and astro‐glial activations were determined by western blotting and immunocytochemistry. We found that MPTP administrated wild type (Wt) mice exhibits oxidative stress by significantly increased level of MDA and activity of SOD and reduced the level of GSH and the activity of GPx when compared with both mast cell deficient (MC‐KO) and GMF‐KO mice. The number of TH‐positive neurons in the ventral tegmental area (VTA), SN and the fibers in STR were significantly reduced and GFAP, IBA1, calpain 1 and ICAM 1 expressions were significantly increased in Wt mice. Similarly, we found that TH, DAT and VMAT2 proteins expression significantly reduced in the SN of Wt mice when compared with both the MC‐KO and GMF‐KO mice. The motor behavior in rotarod and hang test performance significantly reduced Wt mice as compared with both the MC‐KO and GMF‐KO mice. Our study shows that deficiency of GMF and mast cells protects nigrostriatal degeneration via inhibition of astro‐glial activation‐mediated oxidative stress and neuroinflammation in the MPTP mouse model of PD. These results suggest that GMF dependent mast cells activations enhances the detrimental effect of dopaminergic degeneration and its inhibition may be a beneficial therapeutic target of PD and other neurodegenerative disorders that are associated with neuroinflammation, mast cell‐astro‐glial activation‐derived cell death.Support or Funding InformationThis work was supported by Veteran Affairs Merit Award I01BX002477 and National Institutes of Health Grants AG048205 and NS073670.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.