Corticotrophin-releasing factor (CRF) is important in regulating behavioral and physiological responses to stressors. We sought to specifically understand the role of CRF neuron regulation in fear and stress responses by utilizing transgenic mice lacking NMDA-mediated excitation within CRF neurons.

In experiment 1 we fear conditioned mice by pairing an auditory tone with an aversive foot shock. One day later we measured fear responses and extinction to the tone in the absence of shock. Wildtype males and all females exhibited normal extinction, whereas knockout males showed enhanced fear expression and impaired fear extinction .

In experiment 2 we examined naïve social interaction by measuring the amount of time experimental mice spent interacting with novel target mice versus unoccupied chambers. Knockout males displayed increased sociability compared to wildtype males, whereas females showed no significant genotype effect.

Finally, in experiment 3 we tested the socialization behavior of male mice after defeat stress. Defeats occurred 4 times per day for two consecutive days (8 total defeats), and involved placing an experimental mouse in the home cage of an aggressor mouse that naturally defends its territory. Twenty-four hours after the last defeat, social interaction testing indicated that knockout males susceptible to defeats exhibited enhanced social withdrawal compared to wildtypes.

Together, these experiments revealed differences in fear expression, sociability, and stress responsiveness in a genotype-specific manner in males, but not in females. These findings indicate that within CRF neurons, NMDA receptor signaling plays an essential role in inhibiting risk-related behaviors in a sex-specific manner.