Immediately following a disturbing experience, specific contextual cues associated with the experience can elicit the initial unpleasant reaction (e.g., fear). Over time, cues that are similar, but not identical, to the original associated cues can also instigate an aversive response. This phenomenon is known as context generalization, a pathological form of which is frequently a symptom of anxiety disorders such as social anxiety and post-traumatic stress disorder. In order to advance understanding of the pathologies underlying these anxiety disorders, we sought to identify means to re-establish context specificity and reduce fear generalization. Mice and rats were trained in context fear conditioning, and tested at a long interval with or without exposure to the training context. We demonstrated that fear generalization was reduced through a re-exposure to the training context in rats, but not in mice. Our data indicate fear generalization was reduced in both male and female rats. However, fear generalization was only reduced in male mice, but not in females. As females are more susceptible to anxiety disorders, understanding the sex difference in fear generalization is crucial to determining sex-specific treatments for anxiety disorders.
Loss of NMDA receptor function in corticotrophin-releasing factor neurons sex-dependently enhances fear and increases sensitivity to social stress, yet reduces social anxiety03/11/2015
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.
Estradiol, likely through aromatization of testosterone, attenuates fear generalization in male rats03/11/2015
Generalization is a symptom of many anxiety disorders, and females are 60% more likely to suffer from anxiety disorders than males. We have previously demonstrated that female rats display accelerated rates of contextual fear generalization compared to males; a process driven, in part, by activation of ERb. The current study attempted to determine the impact of estrogens on contextual fear generalization in male rats. For experiment 1, adult male rats were gonadectomized (GDX) and implanted with a capsule containing testosterone proprionate (T), estradiol (E2), dihydrotestosterone proprionate (DHT), or an empty capsule. These data suggest that T attenuates fear generalization in males likely through the aromatization of T into estradiol as animals treated with the non-aromatizable androgen, DHT, displayed significant generalized fear responses. In experiment 2, experiment 1 was replicated with acute injections administered 24 hours before training. Animals treated acutely with E2 injections displayed reduced fear generalization similar to those observed in experiment 1. These data suggest that estradiol modulates fear generalization in a bi-direction, sex-dependent manner.