Abstract: Learning to fear threats in the environment is highly adaptive. However， this form of learning can also lead to pathological fear memories that fuel disorders of fear and anxiety，such as panic disorder and post-traumatic stress disorder （PTSD） in humans. Increasingly evidence suggests that the ventral medial prefrontal cortex （vmPFC） is involved in fear retrieval and fear extinction. However，no studies have as yet addressed the network plasticity in fear extinction. Here，we studied the role of PV network plasticity in the extinction of cued fear memory and the underlying molecular mechanisms. vmPFC is composed of prelimbic cortex （PL） and infrelimbic cortex （IL）. We found that fear extinction induced a low PV-network configuration （low PV and GAD67 expression） in IL cortex but not PL cortex. To characterize the molecular mechanisms that underlie PV network plasticity in fear extinction，we analyzed an
amount of molecules that are known to regulate GABAergic neuronal development and found that fear extinction induced an increased expression of NRG1. We would ask whether NRG1 regulates fear extinction. We found that neutralizing endogenous NRG1，inhibition，or genetic deletion of ErbB4，the functional receptor of NRG1，in the IL cortex impaired fear extinction，whereas local infusion of exogenous NRG1 in this region enhanced fear extinction. Specific ablation of ErbB4 in PV positive neurons impaired fear extinction. Notably，overexpression of ErbB4 in the IL cortex is sufficient to reverse impaired fear extinction in PV-Cre；ErbB4-/- mice. Together，these results demonstrated that NRG1 facilitated fear extinction through ErbB4 receptors on PV neurons.
Next，we investigated the role of NRG1 signaling in modulating PV-network plasticity. We found that NRG1 induced a low PV-network configuration in IL cortex. In contrast，administration of ecto-ErbB4 to neutralize endogenous NRG1 induced a high PV-network configuration，suggesting an involvement of NRG1 signaling in regulating PV-network plasticity. Selective knockout or knockdown of ErbB4 receptors from PV neurons induced a high PV-network configuration in the IL cortex while NRG1 failed to induce a low PV-network configuration in PV-Cre；ErbB4-/- mouse. These observations suggested that NRG1 regulated PV- network plasticity through ErbB4. Does NRG1 regulate fear extinction through modulating PV-network plasticity？ We found that pharmacogenetic activation of PV neurons induced a high PV-network，and reversed the facilitation of fear extinction by NRG1. Similarly，pharmacogenetic inhibition of PV neurons induced a low PV-network，and reversed the inhibitory effect of ecto-ErbB4 on fear extinction. These results suggested that NRG1 facilitated fear extinction by regulating PV- network plasticity. Taken together，we provided evidence that NRG1-ErbB4 signaling in IL is essential for regulating fear extinction via modulation of PV-networks plasticity and suggested that this signaling may be a target for the treatment of fear-related diseases.