MicroRNA regulation of fear memory

Extinction, the gradual reduction in conditioned fear responses generated by repeated presentation
of a non-reinforced conditioned stimulus, is a process of inhibitory learning with enormous clinical
importance, since it represents the explicit model of behavioural therapy for phobia and post-
traumatic stress disorder. Understanding the neural mechanisms by which fear can be extinguished
is crucial if we are to develop better therapeutic protocols for the treatment of affective disorders.
MicroRNAs (miRs) are a newly discovered family of endogenous small non-coding RNAs (~23
nucleotides long) that regulate gene function either by degradingtarget mRNAs or by directly binding
to the 3旦TR of protein-coding genes, resulting in post-transcriptional silencing. In the past decade,
several lines of evidence have implicated various miRs in the pathogenesis of human braindisorders,
including schizophrenia; however, their functional role in fear-related learning and memory remains
unknown. We have discovered that the brain-specific microRNA, miR-128b, is highly expressed within
excitatory cortical neurons that express its host gene, regulator of calcium signaling (RCS), and that
are innervated by dopamine within the infralimbic prefrontal cortex (ILPFC); a brain region heavily
involved in encoding fear extinction memories. We also show that miR-128b is necessary for the
formation of fear extinction memory, compared with miR134 and miR140, which show a non-
specific or no association with fear extinction memory, respectively. Using an in vivo lentiviral-
mediated gene transfer approach, we further demonstrate that miR128b negatively regulates the
function of several plasticity-related genes associated with the acquisition and retrieval of
conditional fear. Our results suggest that the transient disruption of fear-related genes by miR-
128b at the time of retrieval and during extinction training may provide a molecular switch which
serves to facilitate the transition from retrieval of the original fear toward the formation of a fear
extinction memory.