Pavlovian fear conditioning, which offers the advantage of simplicity in both the control of conditional and unconditional stimuli (CS, US) presentation and the analysis of specific conditional and unconditional responses (CR, UR) in a controlled laboratory setting, has been the standard model in basic and translational fear research. Despite 100 years of experiments, the utility of fear conditioning has not been trans-situationally validated in real-life contexts. We thus investigated whether fear conditioning readily occurs and guides the animal’s future behavior in an ecologically-relevant environment. To do so, Long-Evans rats foraging for food in an open arena were presented with a tone CS paired with electric shock US to their dorsal neck/body that instinctively elicited escape UR to the safe nest. On subsequent test days, the tone-shock paired animals failed to exhibit fear CR to the CS. In contrast, animals that encountered a realistic agent of danger (a looming artificial owl) paired with a shock, simulating a plausible predatory strike, instantly fled to the nest when presented with a tone for the first time. These results highlight the possibility of a nonassociative, rather than standard associative, fear process providing survival function in life-threatening situations that animals are likely to encounter in nature.

Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable and unpredictable), can measurably affect subsequent neuronal properties and cognitive functioning of the hippocampus. At the cellular level, stress has been shown to alter hippocampal synaptic plasticity, spike and local field potential activity, dendritic morphology, neurogenesis, and neurodegeneration. At the behavioral level, stress has been found to impair learning and memory for declarative (or explicit) tasks that are based on cognition, such as verbal recall memory in humans and spatial memory in rodents, while facilitating those that are based on emotion, such as differential fear conditioning in humans and contextual fear conditioning in rodents. These vertically related alterations in the hippocampus, procedurally observed after subjects have undergone stress, are generally believed to be mediated by recurrently elevated circulating hypothalamic-pituitary-adrenal (HPA) axis effector hormones, glucocorticoids, directly acting on hippocampal neurons densely populated with corticosteroid receptors. The main purposes of this review are to (i) provide a synopsis of the neurocognitive effects of stress in a historical context that led to the contemporary HPA axis dogma of basic and translational stress research, (ii) critically reappraise the necessity and sufficiency of the glucocorticoid hypothesis of stress, and (iii) suggest an alternative metaparadigm approach to monitor and manipulate the progression of stress effects at the neural coding level. Real-time analyses can reveal neural activity markers of stress in the hippocampus that can be used to extrapolate neurocognitive effects across a range of stress paradigms (i.e., resolve scaling and dichotomous memory effects issues) and understand individual differences, thereby providing a novel neurophysiological scaffold for advancing future stress research.