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Abstract
Learned safety is a fear inhibitory mechanism, which regulates fear responses, promotes episodes of safety and generates positive affective states. Despite its potential as experimental model for several psychiatric illnesses, including post-traumatic stress disorder and depression, the molecular mechanisms of learned safety remain poorly understood, We here investigated the molecular mediators of learned safety, focusing on the characterization of miRNA expression in the basolateral amygdala (BLA). Comparing levels of 22 miRNAs in learned safety and learned fear trained mice, six safety-related miRNAs, including three members of the miR-132/-212 family, were identified. A gain-of-function approach based upon in-vivo transfection of a specific miRNA mimic, and miR-132/212 knock-out mice as loss-of-function tool were used in order to determine the relevance of miR-132 for learned safety at the behavioral and the neuronal functional levels. Using a designated bioinformatic approach, PTEN and GAT1 were identified as potential novel miR-132 target genes and further experimentally validated. We here firstly provide evidence for a regulation of amygdala miRNA expression in learned safety and propose miR-132 as signature molecule to be considered in future preclinical and translational approaches testing the transdiagnostic relevance of learned safety as intermediate phenotype in fear and stress-related disorders.
Highlights
As fear can be generated and increased by learning processes, likewise learned fear inhibitory mechanisms exist
The direct comparison to a learned fear group trained in a paradigm matching in numbers the conditioned stimulus (CS) and unconditioned stimulus (US) presentations used for the learned safety protocol was selected as relevant and most suitable control group accounting for effects induced both by the experience of the CS and US, as used in our previous study[2]
The present study shows that learned safety is associated with a distinguished signature of 6 miRNAs in the mouse basolateral amygdala (BLA)
Summary
As fear can be generated and increased by learning processes, likewise learned fear inhibitory mechanisms exist. A detailed electrophysiological characterization revealed the presence of specific “safety neurons” in the basal amygdala, which could be further distinguished by either a selective response to safety cues alone or activation in response to safety cues coupled to a rewarding stimulus[9]. This cellular analysis further complemented previously obtained behavioral data[2,3,7] supporting the notion of shared neural mechanisms of safety and reward processing in the amygdala. How gene expression is regulated in response to the recall of learned safety has so far remained unexplored, which led us to examine the involvement of specific microRNAs (miRNAs) as molecular mediators. The BLA exert crucial functions in fear extinction, a learned safety-related fear inhibitory paradigm, proposing an involvement of miRNAs in inhibitory emotional learning and memory[16,17]
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