Role of MicroRNAs in Anxiety and Anxiety-Related Disorders.

MicroRNAs as critical regulators of gene expression important for functions including neuronal development, synapse formation, and synaptic plasticity have been linked with the regulation of neurobiological systems that underlie anxiety processing in the brain. In this chapter, we give an update on associative evidence linking regulation of microRNAs with anxiety- and trauma-related disorders. Moving beyond correlative research, functional studies have emerged recently that explore causal relationships between microRNA expression and anxiety-like behavior. It has been demonstrated that experimental up- or downregulation of the candidate microRNAs in important nodes of the anxiety neurocircuitry can indeed modulate anxiety-related behavior in animal models. Improved methodologies for assessing microRNA-mediated modulation have aided such functional studies, revealing a number of anxiety-regulating microRNAs including miR-15a, miR-17-92, miR-34, miR-101, miR-124, miR-135, and miR-155. Important functional target genes of these identified microRNAs are associated with specific neurotransmitter/neuromodulator signaling, neurotrophin (e.g., BDNF) expression and other aspects of synaptic plasticity, as well as with stress-regulatory/hypothalamic-pituitary-axis function. Furthermore, microRNAs have been revealed that are regulated in distinct brain regions following various anxiety-attenuating strategies. These include pharmacological treatments such as antidepressants and other drugs, as well as non-pharmacological interventions such as fear extinction/exposure therapy or positive stimuli such as exposure to environmental enrichment. These are first indications for a role for microRNAs in the mechanism of action of anxiolytic treatments. As research continues, there is much hope that a deeper understanding of the microRNA-mediated mechanisms underlying anxiety-related disorders could open up possibilities for future novel biomarker and treatment strategies.