Regulation of fear-related behavior by cortical metabotropic glutamate 5 receptors (mGluR5)

Aims: Metabotropic glutamate 5 receptors (mGluR5) signaling pathway has been implicated in the maintenance of the excitation/inhibition (E/I) balance in neuronal networks, and thus to contribute to appropriate processing of emotional information and regulation of fear-related behavior. However, numerous gaps remain in our current knowledge of the neural substrates of fear, in particular, the assessment of the role of those receptors in one of the central nodes of the brain neurocircuitry for fear, namely the medial prefrontal cortex (mPFC). The aim of this study was to assess the impact of photopharmacological manipulations of mGluR5 in the mPFC on the expression of fear-like behavior.Methods: Experiments were performed on fear conditioned adult mice, implanted with opto-cannulae into the mPFC. The mGluR5 photoswitchable Negative Allosteric Modulator (NAM) Alloswitch-1 was injected systemically and its activity was abolished by violet light illumination selectively in the mPFC, during the pairing of the conditioned (tone) and unconditioned (foot-shock) stimuli. The expression of fear-related behavior (freezing) was then evaluated upon fear retrieval and extinction.Results: Our findings show that the decreased fear expression after brain-wide inhibition of mGluR5 (during fear acquisition) was not reversed upon the release of mGluR5 inactivation in the mPFC (site-specific inactivation of Alloswitch-1). However, inactivation of Alloswitch-1 in mPFC affected the retrieval of the fear memory.Conclusion: Our preliminary findings confirm the role of mGluR5 in the acquisition of fear learning and suggest that this receptor critically influences the mPFC neural circuits involved in the retrieval of the fear memory.