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Contextual learning is evident with repeated experiences with agents and treatments that induce frank illness and interoceptive stress. Here, we examined whether acute treatment with mild interoceptive stressors (low doses of pyridostigmine bromide (PB), neostigmine bromide (NB), and interleukin (IL)-1beta) may serve as unconditional stimuli supporting contextual learning. Rats were exposed to interoceptive and exteroceptive stressors in contexts distinguished by visual or olfactory cues. Acoustic startle responses (ASRs) were measured the day following exposure and 2 weeks thereafter, without delivery of the unconditional stimuli. The appearance, form, and duration of startle potentiation depended on the distinguishing features of the context and the nature of the interoceptive stressor. Rats given cholinesterase inhibitors (PB and NB), but not IL-1beta or exposed to an exteroceptive stressor, exhibited exaggerated ASRs in a novel context distinguished by visual cues. Treatment with either PB or IL-1beta led to potentiated ASRs in the presence of odors congruent with those experiences during exposure to the stressor. Startle potentiation by odor was still apparent 2 weeks after treatment. For contexts differentiated by visual stimuli, cholinomimetics transiently alter reactivity within novel contexts. In the case of contexts differentiated by odors, learning is apparent at least 2 weeks after acute treatment of cholinomimetics and IL-1beta. Contextual learning and changes in reactivity consequent to mild interoceptive stressors such as PB may play a role in the development of nonspecific symptoms typical of unexplained illnesses, such as Gulf War Illness.

Mild Interoceptive Stressors Affect Learning and Reactivity to Contextual Cues: Toward Understanding the Development of Unexplained Illnesses