Stressor Identity Shapes Reactivity To Subsequent Stress

Abstract

Extensive work has established that exposure to a single acute stressor can have profound impacts on future reactivity to new stressors, including enhanced acquisition of new fear. The impact of stressor type on development of stress sensitization, however, remains unclear. We investigated whether fundamentally different acute stressors (shock, social defeat, or restraint stress) differ in ability to sensitize acquisition of a new, contextually distinct fear memory in adult male mice two weeks following stress exposure. Stressor subtype differentially sensitized new fear learning; specifically, shock and social defeat - but not restraint stress - led to enhanced recall of a new shock-paired fear memory. We also compared how stressor subtypes differentially engage the brain-periphery interactions that regulate stress responsivity. Notably, restraint stress, which did not lead to fear sensitization to foot shock, drove similar or even greater corticosterone release than other stressors, suggesting that the neuroendocrine response to the original stressor is dissociable from development of a behavioural fear sensitization response. Using the immediate-early gene FOS as a marker of neural activity, all conditions - including the context-only control condition - activated a similar number of neurons in the basolateral amygdala. In contrast, only stressful conditions activated the paraventricular nucleus of the hypothalamus, and restraint stress selectively spared activation of the dorsal hippocampus. These data collectively suggest that future responses to stress depend critically on the identity of previously experienced stressors, rather than simply on prior exposure to stress, establishing a powerful comparative model for investigating the specific mechanisms underlying stress-enhanced fear learning.