Understanding Alcoholism Through microRNA Signatures in Brains of Human Alcoholics.

Hypothetical model for neuroimmune-related actions of miRNAs in brain of human alcoholics (e.g., in microglia). Bacterial lipopolysaccharides (LPS) from commensal bacteria, for example, could leak into the bloodstream due to gut leakiness induced by alcohol consumption. A compromised blood brain barrier due to high ethanol concentration in the blood will consequently allow LPS to reach the brain and trigger TLR signaling cascades that activate nuclear factor kappa B (NFκB) and induce the transcription of a variety of pro-inflammatory genes (e.g., cytokines), as well as miRNA genes. Newly synthesized pro-inflammatory factors are secreted to unleash a systemic neuroinflammatory response and to maintain a positive feedback loop in same activated cell. These second round of pro-inflammatory factor production is achieved through the expression of alternative cytokine receptors in the activated cell, which signal back to the nucleus through the JAK/STAT pathway to induce production of additional pro-inflammatory factors (e.g., interferons) and miRNA genes. To avoid over-amplification of these signals and excessive inflammation due to hyper-responsiveness to LPS insult, specific miRNAs (e.g., members of the miR-146, miR-152, and let-7 families) are consequently upregulated in order to suppress TLR4/CXCR4 signaling through inhibition of multiple cascade transducers such as IL1 receptor-associated kinases (IRAKs), TNF receptor-associated factor 6 (TRAF6), and TLR4/CXCR4 themselves, among others. As a compensatory reaction, other miRNAs (e.g., miR-203) that activate the alternative JAK/STAT pathway are also upregulated in an effort to maintain the immune-activated state of the specific cell subtype while promoting a benign, contained inflammatory response. Concomitantly, immune-activated cells implement miRNA-mediated epigenetics mechanisms, such as DNA methylation and histone methylation and/or acetylation) that ensure chromatin modification and global changes in gene expression that allow for long-term homeostatic changes and cellular adaptations under the particular environmental conditions. Expectedly, miRNAs that target epigenetic factors are also activated in order to control and/or fine-tune the ongoing remodeling of the cellular epigenome.

Hypothetical model for synaptic-related actions of miRNAs in brain of human alcoholics (e.g., in neurons). Ethanol can directly or indirectly affect multiple neurotransmitter receptors at the neuronal synapse and activate reward circuits conducive to multiple forms of neuronal plasticity, which in turn, convert the drug-induced signals into long-term alterations in behavior (e.g., alcohol dependency). The receptors affected on a particular synapse depend on the neuronal subtype and the specific subset of receptors expressed. For simplicity, several receptors such as GABAR, NMDAR, AChR, μOR, DRD, and β2AR, were diagramed as co-localized on the same synapse in the cartoon, but this is probably not the case in reality. miRNAs transported to and enriched in the synapses are locally processed by resident miRNA-ribonucleoprotein (miRNP) complexes (containing Dicer and FXR1P among other factors) and exert predominately inhibitory effects on mRNA targets also present at the specific synapses. Members of miRNA families, such as let-7, miR-1, miR-101, miR-140, and several others, downregulate the activity of neurotransmitter receptors by directly targeting respective mRNAs or by interfering with synaptic endocytosis (e.g., through targeting of dynamin and α-synuclein mRNAs). In addition, synaptic miRNAs implement negative feedback loops (through targeting of dicer and FXR1 mRNA, among other miRNA biogenesis-related factors) that auto-regulate their own availability. Such feedback loops ensure a balanced homeostatic control of a variety of synaptic functions. Concomitantly, cells implement miRNA-mediated epigenetics mechanisms, such as DNA methylation and histone methylation and/or acetylation, that ensure chromatin modification and global changes in gene expression that allow for long-term homeostatic changes and cellular adaptations under the particular environmental conditions. Expectedly, miRNAs that target epigenetic factors are also activated in order to control and/or fine-tune the ongoing remodeling of the cellular epigenome.