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MicroRNA Pathways Linking Stress, Brain Disease, and the Immune System

MicroRNA (miRNA) are small non-coding RNA molecules that contain about 22 nucleotides and function as silencers and regulators of mRNA that conveys genetic information from DNA, to specify the amino acid sequence of the protein products of gene expression through the process known as post-transcription gene regulation.  Recent research has now shown their importance  in the link between dysregulation of one particular MiRNA, miR-124, and stress and neuro-immunity in a variety of brain disorders.

Mental stress modifies neuro-transmission by changing the profile of certain miRNA’s in the hippocampus, considered the center of emotion, memory, and autonomic nervous system function. It also modifies function in another part of the brain, the paraventricular nucleus (PVN), associated thyroid releasing hormone, leptin, gastrin, neuropeptide y, sympathetic nervous system regulation, and the control of rage. Experimental animals affected by psychological stress after experimental infection, chemical toxicity, and aging factors, altered their immune response activation associated with upregulation of miR-124.  Overexpression of miR-124 significantly inhibited expression of 100’s of stress-induced transcripts detected by microarray including the glucocorticoid receptor (GR), with profound effects on a variety of physiological processes, including adaptation to acute and chronic stress by decreasing GR mRNA in the PVN.  By regulating GR, miR-124 affects a variety of systemic stress responses.

MicroRNA also have unique expression profiles in cells of the immune systems functioning as ‘negotiators’ between the CNS and immune system.  One such pathway, the cholinergic anti-inflammatory pathway, which acts as a link between the brain and the immune system in response to an immune challenge, controls the inflammatory response through interaction with nicotinic acetylcholine receptors expressed on macrophages. MicroRNA are necessary for the cholinergic anti-inflammatory action by inhibiting the production of pro-inflammatory cytokines.

Specialized macrophages called microglial cells that reside in the brain and spinal cord form the frontline defense of the immune system. Utilizing a mouse model of multiple sclerosis (MS), investigators showed that microglial miR-124 expression decreased by almost 70% during the course of the disease. If microRNA are promoters of microglial quiescence, and suppresses experimental autoimmune encephalitis (EAE) by deactivating macrophages, it comes as no surprise that treatment of affected mice at the onset their disease ameliorated their symptoms and enhanced their recovery. 
By triggering a large set of orchestrated genes, the combined actions of miR-124 in attenuating microglia and inhibiting the neuro-immune response to stress, toxins, and aging, have implications for microRNA in slowing or safely reversing such human diseases such as MS, Parkinson disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and other brain disorders. 

Sun Yang, Muo Zhu-Min, Guo Ziu-Ming, et al. An updated role of microRNA-124 in central nervous system disorders: a review. Frontiers of Cellular Neuroscience. https://doi.org/10.3389/fncel.2015.00193