Neuropathic pain caused contextual fear generalization by reducing RIN1 expression in dorsal hippocampal CA1 pyramidal neurons

Conditioned fear learning enables an organism to use sensory cues to predict potential threats and take adaptive responses to avoid bodily harm. The generalization of fear to safety situations is a common cognitive disorder after traumatic stress. The current study investigated the effect of nerve injury on the fear memory in the mice of both sexes, and found that the neuropathic pain correlated with the contextual fear generalization, a maladaptive fear response to non-threatening environments. Our data showed that Ras and Rab interactor 1 (RIN1), a neuron-specific protein in the brain, was critically involved in the modification of fear memory. Peripheral nerve injury reduced the expression of RIN1 in the dorsal CA1 pyramidal neurons, which led to an enhanced synaptic distribution of N-methyl-D-aspartate (NMDA) subtype glutamate receptors containing GluN2B subunit (GluN2B receptors). Microinjection of GluN2B receptor-selective antagonist ifenprodil into the dorsal CA1 region attenuated the generalized contextual fear without significant influence on the auditory fear memory. Targeted knockdown of RIN1 in the dorsal CA1 pyramidal neurons mimicked the nerve injury by inducing the GluN2B receptor-dependent generalization of contextual fear. These data implicated the contextual fear generalization as one of the anxiety-related disorders during neuropathic pain and indicated an important role of RIN1 in the negative control over the generalized fear.