Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes.

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

Effects of chlordiazepoxide on predator odor-induced reductions of playfulness in juvenile rats.

The extent to which a non-sedative dose of chlordiazepoxide (CDP) is able to modify the behavioral responses toward a predator odor was assessed in juvenile rats. Play behavior was suppressed and defensive behaviors were enhanced in the presence of a collar previously worn by a cat, when tested 24 h later in the same context as that where the exposure occurred, and when tested in a context different than that in which the exposure occurred for up to 3 h after exposure. CDP had no effect on the ability of cat odor to suppress play when rats were tested in the presence of the odor or when tested 24 h later in the same context where that exposure occurred. When rats were exposed to a worn cat collar in their home cage and tested in a different context CDP attenuated the ability of cat odor to reduce one measure of play (nape contacts) but not another measure (pins). Rats had an opportunity to hide during testing and CDP either decreased hiding or increased risk assessment from within the hide box in all of the testing scenarios. These data suggest that CDP can alter the defensive strategy used by juvenile rats that are confronted with a predatory threat and can also lead to an earlier return to pre-threat levels of playfulness when that threat becomes less immediate.